Novel immunotherapeutic agents

ABSTRACT

Cyano and carboxy derivatives of substituted styrenes are inhibitors of tumor necrosis factor α, nuclear factor κB, and phosphodiesterase and can be used to combat cachexia, endotoxic shock, retrovirus replication, asthma, and inflammatory conditions. A typical embodiment is 3,3-bis-(3,4-dimethoxyphenyl)acrylonitrile.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a divisional of Ser. No. 08/909,201 filed Aug. 11, 1997which is a continuation-in-part of Ser. No. 08/695,599 filed Aug. 12,1996.

BACKGROUND OF THE INVENTION

[0002] This invention relates to a method of reducing the level ofcytokines and their precursors in mammals and to compounds andcompositions useful therein. In particular, the invention pertains to aclass of compounds which mediate the action of phosphodiesterases,particularly PDE III and PDE IV, and the formation of TNFαand NFκB.

[0003] Tumor necrosis factor alpha, (TNFo) is a cytokine which isreleased primarily by mono-nuclear phagocytes in response toimmunostimulators. When administered to animals or humans, TNFαcan causeinflammation, fever, cardiovascular effects, hemorrhage, coagulation,and acute phase responses similar to those seen during acute infectionsand shock states.

[0004] The nuclear factor κB (NFκB) is a pleiotropic transcriptionalactivator (Lenardo, et al., Cell 1989, 58, 227-29) which has beenimplicated in a variety of disease and inflammatory states. NFκB isthought to regulate cytokine levels including, but not limited to, TNFαand to be an activator of HIV transcription (Dbaibo et al, J. Biol.Chem. 1993, 17762-66; Duh et al., Proc. Natl. Acad Sci. 1989, 86,5974-78; Bachelerie et al. Nature 1991, 350, 709-12; Boswas et al., J.Acquired Immune Deficiency Syndrome 1993, 6, 778-786; Suzuki et al.,Biochem. And Biophys. Res. Comm. 1993, 193, 277-83; Suzuki et al.,Biochem. And Biophys. Res Comm. 1992, 189, 1709-15; Suzuki et al.,Biochem. Mol. Bio. Int. 1993, 31(4), 693-700; Shakhov et al. 1990, 171,3547; and Staal et al., Proc. Natl. Acac Sci. USA 1990, 87, 9943-47).Thus, inhibition of NFκB binding can regulate transcription of cytokinegene(s) and through this modulation and other mechanisms be useful inthe inhibition of a multitude of disease states. TNFα and NFκB levelsare influenced by a reciprocal feedback loop.

[0005] Many cellular functions are mediated by levels of adenosine3′,5′-cyclic monophosphate (cAMP). Such cellular functions cancontribute to inflammatory conditions and diseases including asthma,inflammation, and other conditions (Lowe and Cheng, Drugs of the Future,17(9), 799-807, 1992). It has been shown that the elevation of cAMP ininflammatory leukocytes inhibits their activation and the subsequentrelease of inflammatory mediators, including TNFα and NFκB. Increasedlevels of cAMP also leads to the relaxation of airway smooth muscle. Theprimary cellular mechanism for the inactivation of cAMP is thebreak-down of cAMP by a family of isoenzymes referred to as cyclicnucleotide phosphodiesterases (PDE), of which seven are known. It isrecognized, for example, that the inhibition of PDE type IV isparticularly effective in both the inhibition of inflammatory mediatorrelease and the relaxation of airway smooth muscle. Thus, compoundswhich inhibit PDE IV exhibit the desirable inhibition of inflammationand relaxation of airway smooth muscle with a minimum of unwanted sideeffects, such as cardiovascular or anti-platelet effects. It is nowknown that inhibition of TNFα production is a consequence of inhibitionof PDE IV. L. J. Lombardo, Current Pharnaceutical design, 1, 255-268(1995).

[0006] Excessive or unregulated TNFα production has been implicated in anumber of disease conditions. These include endotoxemia and/or toxicshock syndrome {Tracey et al., Nature 330, 662-664 (1987) and Hinshaw etal., Circ. Shock 30, 279-292 (1990)}; cachexia {Dezube et al., Lancet,335 (8690), 662 (1990)}; and Adult Respiratory Distress Syndrome (ARDS)where TNFα concentrations in excess of 12,000 pg/milliliters have beendetected in pulmonary aspirates from ARDS patients {Millar et al.,Lancet 2 (8665), 712-714 (1989)). Systemic infusion of recombinant TNFαalso resulted in changes typically seen in ARDS {Ferrai-Baliviera etal., Arch. Surg. 124(12), 1400-1405 (1989)}.

[0007] TNFα also appears to be involved in bone resorption diseases,including arthritis where it has been determined that when activated,leukocytes will produce a bone-resorbing activity, and data suggeststhat TNFα contributes to this activity {Bertolini et al., Nature 319,516-518 (1986) and Johnson et al., Endocrinology 124(3), 1424-1427(1989)}. It has been determined that TNFα stimulates bone resorption andinhibits bone formation in vitro and in vivo through stimulation ofosteoblast formation and activation in combination with inhibition ofosteoblast function. Although TNFα may be involved in many boneresorption diseases, including arthritis, the most compelling link withdisease is the association between production of TNFα by tumor or hosttissues and malignancy associated hypercalcemia {Calci. Tissue Int. (US)46 (Suppl.), S3-10 (1990)}. In Graft versus Host Reaction, increasedserum TNFα levels have been associated with major complicationsfollowing acute allogenic bone marrow transplants {Holler et al., Blood,75(4), 1011-1016 (1990)}.

[0008] Cerebral malaria is a lethal hyperacute neurological syndromeassociated with high blood levels of TNFα and is the most severecomplication occurring in malaria patients. Levels of serum TNFαcorrelated directly with the severity of the disease and the prognosisin patients with acute malaria attacks {Grau et al., N. Engl. J. Med 320(24), 1586-1591(1989)}.

[0009] Macrophage-induced angiogenesis is known to be mediated by TNFα.Leibovich et al. {Nature, 329, 630-632 (1987)} showed TNFα induces invivo capillary blood vessel formation in the rat cornea and thedeveloping chick chornoallantoic membranes at very low doses and suggestTNFα is a candidate for inducing angiogenesis in inflammation, woundrepair, and tumor growth. TNFα production also has been associated withcancerous conditions, particularly induced tumors {Ching et al., Brit. JCancer, (1955) 72, 339-343, and Koch, Progress in Medicinal Chemistry,22, 166-242 (1985)}.

[0010] TNFα also appears to play a role in the area of chronic pulmonaryinflammatory diseases. The deposition of silica particles leads tosilicosis, a disease of progressive respiratory failure caused by afibrotic reaction. Antibodies to TNFα completely blocked thesilica-induced lung fibrosis in mice {Pignet et al., Nature, 344:245-247(1990)}. High levels of TNFα production (in the serum and in isolatedmacrophages) have been demonstrated in animal models of silica andasbestos induced fibrosis {Bissonnette et al., Inflammation 13(3),329-339 (1989)}. Alveolar macrophages from pulmonary sarcoidosispatients have also been found to spontaneously release massivequantities of TNFα as compared with macrophages from normal donors{Baughman et al., J. Lab. Clin. Med. 115 (1), 36-42 (1990)}.

[0011] TNFα is also implicated in the inflammatory response whichfollows reperfusion, called reperfusion injury, and is a major cause oftissue damage after loss of blood flow {Vedder et al., PNAS 87,2643-2646 (1990)}. TNFα also alters the properties of endothelial cellsand has various pro-coagulant activities, such as producing an increasein tissue factor pro-coagulant activity and suppression of theanticoagulant protein C pathway as well as down-regulating theexpression of thrombomodulin {Sherry et al., J. Cell Biol. 107,1269-1277 (1988)}. TNFα has pro-inflammatory activities which togetherwith its early production (during the initial stage of an inflammatoryevent) make it a likely mediator of tissue injury in several importantdisorders including but not limited to, myocardial infarction, strokeand circulatory shock. Of specific importance may be TNFα-inducedexpression of adhesion molecules, such as intercellular adhesionmolecule (ICAM) or endothelial leukocyte adhesion molecule (ELAM) onendothelial cells {Munro et al., Am. J. Path. 135 (1), 121-132 (1989)}.

[0012] TNFα blockage with monoclonal anti-TNFα antibodies has been shownto be beneficial in rheumatoid arthritis (Elliot et al., Int. J.Pharmac. 1995 17(2), 141-145}. High levels of TNFα are associated withCrohn's disease {von Dullemen et al., Gastroenterology, 1995 109(1),129-135) and clinical benefit has been achieved with TNFα antibodytreatment, thus confirming the importance of TNFα in the disease.

[0013] Moreover, it is now known that TNFα is a potent activator ofretrovirus replication including activation of HIV-1. {Duh et al., Proc.Nat. Acad. Sci. 86, 5974-5978 (1989); Poll et al., Proc. Nat. Acad. Sci.87, 782-785 (1990); Monto et al., Blood 79, 2670 (1990); Clouse et al.,J. Immimol. 142, 431-438 (1989); Poll et al., AIDS Res. Hum. ReuoviniL,191-197 (1992)}. AIDS results from the infection of T lymphocytes withHuman Immunodeficiency Virus (HIV). At least three types or strains ofHIV have been identified, ie., HIV-1, HIV-2 and HIV-3. As a consequenceof HIV infection, T-cell mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms, HIV entry into the T lymphocyte requires T lymphocyteactivation. Other viruses, such as HIV-1 and HIV-2, infect T lymphocytesafter T cell activation and such virus protein expression and/orreplication is mediated or maintained by such T cell activation. Once anactivated T lymphocyte is infected with HIV, the T lymphocyte mustcontinue to be maintained in an activated state to permit HIV geneexpression and/or HIV replication. Cytokines, specifically TNFα, areimplicated in activated T-cell mediated HIV protein expression and/orvirus replication by playing a role in maintaining T lymphocyteactivation. Therefore, interference with cytokine activity such as byprevention or inhibition of cytokine production, notably TNFα, in aHIV-infected individual aids in limiting the maintenance of T lymphocyteactivation caused by HIV infection.

[0014] Monocytes, macrophages, and related cells, such as kupffer andglial cells, have also been implicated in maintenance of the HIVinfection. These cells, like T cells, are targets for viral replicationand the level of viral replication is dependent upon the activationstate of the cells (Rosenberg et al., The Immunopathogenesis of HIVInfection, Advances in Immunology, 57 (1989)}. Cytokines, such as TNFα,have been shown to activate HIV replication in monocytes and/ormacrophages {Poli et al. Proc. Natl. Acad. Sci., 87, 782-784 (1990)},therefore, prevention or inhibition of cytokine production or activityaids in limiting HIV progression as stated above for T cells. Additionalstudies have identified TNFα as a common factor in the activation of HIVin vitro and has provided a clear mechanism of action via a nuclearregulatory protein found in the cytoplasm of cells (Osborn, et al., PNAS86, 2336-2340). This evidence suggests that a reduction of TNFαsynthesis may have an antiviral effect in HIV infections, by reducingthe transcription and thus virus production.

[0015] AIDS viral replication of latent HIV in T cell and macrophagelines can be induced by TNFα {Folks et al., PNAS 86, 2365-2368 (1989)}.A molecular mechanism for the virus inducing activity is suggested byTNFα's ability to activate a gene regulatory protein (NFκB) found in thecytoplasm of cells, which promotes HIV replication through binding to aviral regulatory gene sequence (LTR) {Osborn et al., PNAS 86, 2336-2340(1989)}. TNFα in AIDS associated cachexia is suggested by elevated serumTNFα and high levels of spontaneous TNFa production in peripheral bloodmonocytes from patients {Wright et al., J. Immmunol. 141 (1), 99-104(1988)}.

[0016] TNFαhas been implicated in other viral infections, such as thecytomegalia virus (CMV), influenza virus, adenovirus, and the herpesfamily of viruses for similar reasons as those noted.

[0017] It is recognized that suppression of the effects of TNFα can bebeneficial in a variety of conditions and in the past, steroids such asdexamethasone and prednisone as well as polyclonal and monoclonalantibodies {Beutler et al., Science 234, 470-474 (1985); WO 92/11383}have been employed for this purpose. Conditions in which the inhibitionof TNFα is desirable include septic shock, sepsis, endotoxic shock,hemodynamic shock and sepsis syndrome, post ischemic reperfusion injury,malaria, mycobacterial infection, meningitis, psoriasis, congestiveheart failure, fibrotic disease, cachexia, graft rejection, cancer,autoimmune disease, opportunistic infections in AIDS, rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis and other arthriticconditions, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythrematosis, ENL in leprosy, radiation damage, asthma,and hyperoxic alveolar injury.

[0018] The suppression of the action of NFκB in the nucleus can beuseful in the treatment of a variety of diseases including but notlimited to rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,other arthritic conditions, septic shock, septis, endotoxic shock, graftversus host disease, wasting, Crohn's disease, ulcerative colitis,multiple sclerosis, systemic lupus erythrematosis, ENL in leprosy, HIV,AIDS, and opportunistic infections in AIDS.

DETAILED DESCRIPTION

[0019] The compounds of the present invention affect the levels ofphosphodiesterases, TNFα and NFκB and the method involves the regulationof the levels of phosphodiesterases, TNFα and NFκB through theadministration of compounds of the formula:

[0020] in which:

[0021] (a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1,2, or 3, and R¹ is alkyl of one to 10 carbon atoms, monocycloalkyl of upto 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, orbenzocyclic alkyl of up to 10 carbon atoms, or

[0022] (b) X is —CH═and R¹ is alkylidene of up to 10 carbon atoms,monocycloalkylidene of up to 10 carbon atoms, or bicycloalkylidene of upto 10 carbon atoms;

[0023] R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, lower alkyl, lower alkylidenemethyl, lower alkoxy, orhalo;

[0024] R³ is (i) phenyl, unsubstituted or substituted with 1 or moresubstituents each selected independently from nitro, cyano, halo,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to10 carbon atoms, alkylidenemethyl of up to 10 carbon atoms,cycloalkylidenemethyl of up to 10 carbon atoms, phenyl, ormethylenedioxy; (ii) pyridine, substituted pyridine, pyrrolidine,imidizole, naphthalene, or thiophene; (iii) cycloalkyl of 4-10 carbonatoms, unsubstituted or substituted with 1 or more substituents eachselected independently from the group consisting of nitro, cyano, halo,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl;

[0025] each of R⁴ and R⁵ taken individually is hydrogen or R⁴ and R⁵taken together are a carbon-carbon bond;

[0026] Y is —COZ, —C≡N, or lower alkyl of 1 to 5 carbon atoms;

[0027] Z is —OH, —NR⁶R⁶, —R⁷, or —OR⁷;

[0028] R⁶ is hydrogen or lower alkyl; and

[0029] R⁷ is alkyl or benzyl.

[0030] One preferred group are the compounds of Formula I in which R¹ isalkyl, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms; X is—(CH₂)_(n)— or —O—, where n=0, 1, 2, or 3; R² is hydrogen, nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy,halo; and R⁴, R⁵, Y, Z, R⁶, and R⁷ are as therein defined.

[0031] A second preferred group of compounds are those of Formula I inwhich R³ is (i) phenyl or naphthalene, unsubstituted or substituted with1 or more substituents each selected independently from nitro, cyano,halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 5 carbon atoms, alkyl or cycloalkyl of 1 to 10 carbon atoms, alkoxyor cycloalkoxy of 1 to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10carbon atoms, unsubstituted or substituted with one or more substituentseach selected independently from the group consisting of nitro, cyano,halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl.

[0032] Particularly preferred nitriles are compound of the formula:

[0033] wherein:

[0034] (a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1,2, or 3, and R¹ is alkyl of up to 10 carbon atoms, monocycloalkyl of upto 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, orbenzocyclic alkyl of up to 10 carbon atoms, or

[0035] (b) X is —CH═, and R¹ is alkylidene of up to 10 carbon atoms ormonocycloalkylidene of up to 10 carbon atoms;

[0036] R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, lower alkyl, lower alkoxy, or halo; and

[0037] R³ is (i) phenyl or naphthyl, unsubstituted or substituted with 1or more substituents each selected independently from nitro, cyano,halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 5 carbon atoms, alkoxy or cycloalkoxy of 1 to 10 carbon atoms; or(ii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substitutedwith one or more substituents each selected independently from the groupconsisting of nitro, cyano, halo, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxyof 1 to 10 carbon atoms, or phenyl.

[0038] Particularly preferred alkanoic acid derivatives are compound ofthe formula:

[0039] wherein:

[0040] (a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1,2, or 3, and R¹ is alkyl of up to 10 carbon atoms, monocycloalkyl of upto 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, orbenzocyclic alkyl of up to 10 carbon atoms, or

[0041] (b) X is —CH═, and R¹ is alkylidene of up to 10 carbon atoms ormonocycloalkylidene of up to 10 carbon atoms;

[0042] R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, lower alkyl, lower alkoxy, or halo;

[0043] R³ is (i) phenyl or naphthyl, unsubstituted or substituted withone or more substituents each selected independently from nitro, cyano,halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 5 carbon atoms, alkyl or cycloalkyl of 1 to 10 carbon atoms, alkoxyor cycloalkoxy of 1 to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10carbon atoms, unsubstituted or substituted with one or more substituentseach selected independently from the group consisting of nitro, cyano,halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl; and

[0044] Z is —OH, —NR⁶R⁶, R⁷, or —OR⁷ in which R⁶ is hydrogen or loweralkyl; and R⁷ is alkyl or benzyl.

[0045] The term alkyl as used herein denotes a univalent saturatedbranched or straight hydrocarbon chain. Unless otherwise stated, suchchains can contain from 1 to 18 carbon atoms. Representative of suchalkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl,isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like.When qualified by “lower”, the alkyl group will contain from 1 to 6carbon atoms. The same carbon content applies to the parent term“alkane” and to derivative terms such as “alkoxy”.

[0046] The term cycloalkyl as used herein denotes a univalent saturatedcyclic hydrocarbon chain. Unless otherwise stated, such chains cancontain up to 18 carbon atoms. Monocyclicalkyl refers to groups having asingle ring group. Polycycloalkyl denotes hydrocarbon systems containingtwo or more ring systems with two or more ring carbon atoms in common.Benzocycloalkyl signifies a monocyclicalkyl group fused to a benzogroup. Representative of monocycloalkyl groups are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl,cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, cycloheptadecyl, andcyclooctadecyl. Representative of polycycloalkyl includebicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, and bicyclo[2.2.2]octyl.Benzocycloalkyl is typified by tetrahydronaphthyl, indanyl, and1.2-benzocycloheptanyl.

[0047] The compounds can be prepared using methods which are known ingeneral for the preparation of diaryl alkenes. For example, anappropriately substituted bis(aryl) ketone can be treated with a dialkylcyanomethylphosphonate to yield the corresponding bis arylacrylonitrile. This can be hydrolysed to the corresponding carboxylicacid, esters and amides by methods known per se. Alternatively, thesubstituted bis(aryl) ketone can be treated with an alkyl disubstitutedphosphonoacetate or a disubstituted carbamoylmethylphosphonate andlithium hexamethyldisilazide to form the ester or amide, respectively,directly. The substituted bis(aryl) ketone alternatively can be treatedwith the appropriate triphenylphosphite.

[0048] The bis(aryl) ketones also are obtained by methods known per sesuch as for example by Friedel-Crafts acylations with acid chlorides inthe presence of a Lewis acid.

[0049] Representative examples of these compounds include3,3-bis-(3,4-dimethoxyphenyl)-acrylonitrile,3,3-bis-(3-ethoxy-4-methoxyphenyl)acrylonitrile, methyl3,3-bis-(3-ethoxy-4-methoxyphenyl)-propenoate, methyl3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropenoate,3-(3-propoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3,3-bis-(3-cyclopentoxy-4-methoxyphenyl)acrylonitrile, methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropenoate,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropene,1-(3-cyclopentoxy-4-methoxyphenyl)-1-phenylpropane,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanoate,3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanoate,3,3-bis-(3,4-dimethoxyphenyl)propanenitrile,3,3-bis-(3-ethoxy-4-methoxyphenyl)propanenitrile,3-(3,4-dimethoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-methoxyphenyl)-3-naphthylpropanenitrile,3-(3,4-dimethoxyphenyl)-3-phenylpropanenitrile, and3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)-propanenitrile.

[0050] A further group of preferred compounds include4,4-bis-(3,4-dimethoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-phenylbut-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-cyclopentoxy-4-methoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-indan2-yloxy-4-methoxyphenyl)but-3-en-2-one;4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)but-3-en-2-one;4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one;4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)but-3-en-2-one;4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)-butan-2-one; methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enoate; methyl3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enoate; methyl3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanoate;4-(3-ethoxy-4-methoxyphenyl)-4-(2-furyl)but-3-en-2-one;3-(3-ethoxy-4-methoxyphenyl)-3-(2-furyl)prop-2-enenitrile;3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)but-3-en-2-one;4,4-bis-(3,4-dimethoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)butan-2-one,4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)butan-2-one;4,4-bis-(3-ethoxy-4-methoxyphenyl)but-3-en-2-one;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenylprop-2-enenitrile;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pentan-3-one;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pent-1-en-3-one;1,1-bis-(3,4-dimethoxyphenyl)pentan-3-one;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-propanenitrile;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanenitrile;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enamide,3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl-3-phenyl)propanamide;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanamide;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enamide;3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)prop-2-enamide;3,3-bis-(3-ethoxy-4-methoxyphenyl)prop-2-enamide;3,3-bis-(3,4-dimethoxyphenyl)prop-2-enamide;3,3-his-(3-ethoxy-4-methoxyphenyl)propanamide;3,3-his-(3,4-dimethoxyphenyl)propanamide;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-exo-norbornyloxyphenyl)but-3-en-2-one;3-(3,4-dimethoxyphenyl)-3-(4-methoxy-3-exo-norbornyloxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)prop-2-enenitrile;3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile; and3-(4-aminophenyl)-3-(3-ethoxy-4-dimethoxyphenyl)prop-2-enenitrile

[0051] These compounds may possess one or more centers of chirality andthus can exist as optical isomers. Both the racemates of these isomersand the individual isomers themselves, as well as diastereoisomers whenthere are two or more chiral centers, are within the scope of thepresent invention. The racemates can be used as such or can be separatedinto their individual isomers mechanically as by chromatography using achiral absorbent. Alternatively, the individual isomers can be preparedin chiral form or separated chemically from a mixture by forming saltswith a chiral acid, such as the individual enantiomers of10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid,methoxyacetic acid, tartaric acid, diacetyltartaric acid, malic acid,pyrrolidone-5-carboxylic acid, and the like, and then freeing one orboth of the resolved bases, optionally repeating the process, so as toobtain either or both isomers substantially free of the other; i.e., ina form having an optical purity of >95%. In addition, the compounds inwhich R⁴ and R⁵ taken together are a carbon-carbon bond can exist as cis(Z) and trans (E) isomers.

[0052] The compounds can be used, under the supervision of qualifiedprofessionals, to inhibit the undesirable effects of TNFα, NFκB, andphosphodiesterase. The compounds can be administered orally, rectally,or parenterally, alone or in combination with other therapeutic agentsincluding antibiotics, steroids, etc., to a mammal in need of treatment.Oral dosage forms include tablets, capsules, dragees, and similarshaped, compressed pharmaceutical forms. Isotonic saline solutionscontaining 20-100 milligrams/milliliter can be used for parenteraladministration which includes intramuscular, intrathecal, intravenousand intra-arterial routes of administration. Rectal administration canbe effected through the use of suppositories formulated fromconventional carriers such as cocoa butter.

[0053] Dosage regimens must be titrated to the particular indication,the age, weight, and general physical condition of the patient, and theresponse desired but generally doses will be from about 1 to about 1000milligrams/day as needed in single or multiple daily administration. Ingeneral, an initial treatment regimen can be copied from that known tobe effective in interfering with TNFα activity for other TNFα mediateddisease states by the compounds of the present invention. Treatedindividuals will be regularly checked for T cell numbers and T4/T8ratios and/or measures of viremia such as levels of reversetranscriptase or viral proteins, and/or for progression ofcytokine-mediated disease associated problems such as cachexia or muscledegeneration. If no effect is observed following the normal treatmentregimen, then the amount of cytokine activity interfering agentadministered is increased, e.g., by fifty percent a week.

[0054] The compounds of the present invention can also be used topicallyin the treatment or prophylaxis of topical disease states mediated orexacerbated by excessive TNFα production, such as viral infections, forexample those caused by the herpes viruses or viral conjunctivitis,psoriasis, other skin disorders and diseases, etc.

[0055] The compounds can also be used in the veterinary treatment ofmammals other than humans in need of prevention or inhibition of TNFαproduction. TNFα mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedabove, but in particular viral infections. Examples include felineimmunodeficiency virus, equine infectious anaemia virus, caprinearthritis virus, visna virus, and maedi virus, as well as otherlentiviruses.

[0056] Inhibition of PDE III, PDE IV, TNFα and NFκB by these compoundscan be conveniently assayed using methods known in the art, e.g., enzymeinmmunoassay, radioimmunoassay, immunoelectrophoresis, affinitylabeling, etc., of which the following are typical.

Enzyme-Linked Immunosorbent Assay for TNFα

[0057] PBMC isolation: PBMC from normal donors were obtained byFicoll-Hypaque density centrifugation. Cells were cultured in RPMIsupplemented with 10% AB+ serum, 2 mM L-glutamnine, 100 U/mL penicillinand 100 mg/mL streptomycin.

[0058] PBMC suspensions: Drugs were dissolved in dimethylsulfoxide(Sigma Chemical), further dilutions were done in supplemented RPMI. Thefinal dimethylsulfoxide concentration in the presence or absence of drugin the PBMC suspensions was 0.25 wt %. Drugs were assayed at half-logdilutions starting at 50 mg/mL. Drugs were added to PBMC (10⁶ cells/mL)in 96 wells plates one hour before the addition of LPS.

[0059] Cell stimulation: PBMC (10⁶ cells/mL) in the presence or absenceof drug were stimulated by treatment with 1 mg/mL of LPS from Salmonellaminnesota R595 (List Biological Labs, Campbell, Calif.). Cells were thenincubated at 37° C. for 18-20 hours. Supernatants were then harvestedand assayed immediately for TNFα levels or kept frozen at −70° C. (fornot more than 4 days) until assayed.

[0060] TNFα Determination: The concentration of TNFα in the supernatantwas determined by human TNFα ELISA kits (ENDOGEN, Boston, Mass.)according to the manufacturer's directions.

[0061] Phosphodiesterase can be determined in conventional models. Forexample, using the method of Hill and Mitchell, U937 cells of the humanpromonocytic cell line are grown to 1×10⁶ cells/mL and collected bycentrifugation. A cell pellet of 1×10⁹ cells is washed in phosphatebuffered saline and then frozen at −70° C. for later purification orimmediately lysed in cold homogenization buffer (20 mM Tris-HCl, pH 7.1,3 mM 2-mercaptoethanol, 1 mM magnesium chloride, 0.1 mM ethyleneglycol-bis-(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 1 μMphenylmethylsulfonyl fluoride (PMSF), and 1 μg/mL leupeptin). Cells arehomogenized with 20 strokes in a Dounce homogenizer and supernatantcontaining the cytosolic fraction are obtained by centrifugation. Thesupernatant then is loaded onto a Sephacryl S-200 column equilibrated inhomogenization buffer. Phosphodiesterase is eluted in homogenizationbuffer at a rate of approximately 0.5 mL/min and fractions are assayedfor phosphodiesterase activity −/+ rolipram. Fractions containingphosphodiesterase activity(rolipram sensitive) are pooled and aliquotedfor later use.

[0062] The phosphodiesterase assay is carried out based on proceduredescribed by Hill and Mitchell. The assay is carried out in a totalvolume of 100 μl containing various concentration of test compounds, 50mM Tris-HCl, pH 7.5,5 mM magnesium chloride and 1 μM cAMP of which 1%was ³H cAMP. Reactions are incubated at 30° C. for 30 minutes andterminated by boiling for 2 minutes. The amount of phosphodiesterase IVcontaining extract used for these experiments is predetermined such thatreactions are within the linear range and consumed less than 15% of thetotal substrate. Following termination of reaction, samples are chilledat 4° C. and then treated with 101 μl 10 mg/mL snake venom for 15 min at30° C. Unused substrate then is removed by adding 200 μl of a quaternaryammonium ion exchange resin (AG1-X8, BioRad) for 15 minutes. Samplesthen are spun at 3000 rpm, 5 min and 50 μl of the aqueous phase aretaken for counting. Each data point is carried out in duplicate andactivity is expressed as percentage of control. The IC₅₀ of the compoundthen is determined from dose response curves of a minimum of threeindependent experiments.

[0063] The following examples will serve to further typify the nature ofthis invention but should not be construed as a limitation in the scopethereof, which scope is defined solely by the appended claims.

EXAMPLE 1 3,3-bis-(3,4-Dimethoxyphenyl)acrylonitrile

[0064] A. 3,4,3′,4,′-Tetramethoxybenzophenone

[0065] To a stirred ice bath cooled solution of veratole (2.07 g, 15.0mmol) in 30 mL of methylene chloride under nitrogen was added aluminumchloride (2.20 g, 16.5 mmol). A slight exotherm resulted. To thereaction mixture was then added 3,4-dimethoxybenzoyl chloride (3.01 g,15.0 mmol) and 20 mL of methylene chloride. The reaction was thenallowed to warm to room temperature and then refluxed for 3.5 hours andthen allowed to stir at room temperature for 16 hours. The reactionmixture was then poured into 50 mL of ice water and stirred for 15minutes. This mixture was extracted with methylene chloride (2×25 mLeach) The combined extracts were dried over sodium sulfate andconcentrated in vacuo to afford the crude product as a tan solid. Thecrude product was purified by flash chromatography (silica gel, 4/96ethyl acetate/methylene chloride) to afford 2.97 g (66%) of the productas a white powder: ¹H NMR (CDCl₃) δ 7.4 (m, 4H), 6.91 (m, 2H), 3.97 (s,6H), 3.95 (s, 6H); ¹³C NMR (DMSO-d₆) δ 194.4, 152.5, 148.8, 130.7,124.7, 112.2, 109.7, 56.0. Anal. Calcd for C₁₇H₁₈O₅. Theoretical: C,67.54; H, 6.00. Found: C, 67.42; 11, 6.03.

[0066] B. 3,3-bis-(3′,4′-Dimethoxyphenyl)acrylonitrile

[0067] To an ice bath cooled stirred suspension of sodium hydride (5.0mmol) in 20 mL of tetrahydroflran was added 0.8 mL of diethylcyanomethylphosphonate dropwise via syringe. The mixture was allowed towarm to room temperature and then 3,4,3′,4,′-tetramethoxybenzophenone(1.51 g, 5.00 mmol) and 10 mL of tetrahydrofuran were added. The mixturewas stirred for 5 days and then quenched with 100 mL of H₂O. Thereaction mixture was then extracted with methylene chloride (50 mL and25 mL). The combined extracts were dried over sodium sulfate andconcentrated to afford the crude product as an oil. The crude productwas purified by flash chromatography to afford the product as a whitewax: ¹H NMR (CDCl₃) δ 7.95 (br m, 6H), 5.57 (s, 1H), 3.94 (s, 3H), 3.92(s, 3H), 3.87 (s, 3H), 3.84 (s, 3H); ¹³C NMR (DMSO-d₆) δ 162.4, 151.0,150.5, 148.8, 148.5, 131.8, 129.5, 123.2, 122.2, 118,6, 112.7, 111.4,110.7, 110.7, 91.9, 56.0, 55.9, 55.9.

EXAMPLE 2 cis and trans3-(3,4-Dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)acrylonitrile

[0068] A. 3, 4-Dimethoxy-3-ethoxy-4-methoxybenzophenone

[0069] To an ice bath cooled stirred suspension of3-ethoxy-4-methoxybenzoic acid (0.98 g, 5.0 mmol) in 20 mLmethylenechloride was added oxalyl chloride (0.44 mL, 5.0 mmol) and 2 drops ofN,N dimethylformamide (dimethylformamide). The resulting yellow mixturewas stirred at room temperature for 35 minutes at which time a solutionhad formed. The solution was cooled in an ice bath and veratrole (0 64mL, 5.0 mmol) was added followed by aluminum chloride (0.73 g, 5 5mmol). The ice bath was removed and the mixture was stirred at roomtemperature. The reaction was monitored by HPLC (Waters Nova-Pak/C,8column 3.9×150 mm, 4 micron, mL/min, 35/65 acrylonitrile/0.1% aqueousphosphoric acid and after 37 hours the reaction was complete. Thereaction mixture was poured into 30 mL of ice, stirred for 30 minutesand was then extracted with methylene chloride (3×20 mL). The methylenechloride extracts were washed successively with aqueous sodiumbicarbonate (30 mL), water (2×50 mL) and brine (50 mL). The organiclayer was then dried over magnesium sulfate, filtered and concentratedin vacuo to afford 1.05 g of a brown solid The crude product waspurified by flash column chromatography (silica gel, 5% ethylacetate/methylene chloride) and the resulting product was then dried invacuo (60° C., <1 mmHg) to afford 0.8 g (51%) of the product: mp122-124.5° C.; ¹H NMR (CDCl3) δ 7.48-7.34 (m, 4H),6.98-6 86 (m, 2H),4.16 (q, J=7 Hz, 2H), 3.96 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H),1.49 (t,J=7 Hz, 3H); ¹³C NMR (CDC13) δ 194.4, 152 8, 152.5, 148.8, 148.0, 130.7,130.6, 124.6, 124.5, 113.5, 112.2, 109.9, 109.7, 64.3, 55.9, 55.9, 14.6;HPLC (Waters Nova-Pak/C,8 column, 3.9×150 mm, 4 micron, 1 mL/min, 35/65acrylonitrile/0.1% aqueous phosphoric acid 8 min, 99%; Anal. Calcd forC₁₈H₂₀O₅. Theoretical: C, 68.34; H, 6.37. Found: C, 68.56; H, 6.51.

[0070] B. cis and trans 3-(3,4-Dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)acrylonitrile

[0071] To an ice bath cooled stirred solution ofdiethylcyanomethylphosphonate (0.9 mL, 5.5 mmol) in 15 mL oftetrahydrofuran was added a 1.3 M solution of lithiumhexamethyldisilazide (4.2 niL, 5.5 mmol) in tetrahydrofuran. Thesolution was allowed to warm to room temperature and was stirred for 30minutes and then a slurry of3,4-dimethoxy-3-ethoxy-4-methoxybenzophenone (1.58 g, 5.00 mmol) in 20mL of tetrahydrofuran was added. The reaction mixture was stirred atroom temperature for 21 hours and was then quenched with I 00 mL ofwater. The resulting mixture was extracted with methylene chloride (2×50mL). The combined extracts were washed with water, chied over magnesiumsulfate, and concentrated in vacuo to afford the crude product as anorange oil. The crude product was purified by flash columnchromatography (silica gel, 3% ethyl acetate/methylene chloride) andthen recrystallized from hexane/ethyl. The resulting product was thendried in vacuo (40° C., <I mmHg) to afford 0.6 g (35%) of a white solid:mp 103-106° C.; ¹H NMR (CDCl₃) δ 7.10-6.75 (m, 6H), 5.55 (s, 1H),4.17-3.76 (m, 11H), 1.54-1.36 (m, 3H), ¹³C NMR (CDCl₃) δ 162.5, 151.0,150.8, 150.5, 148.8, 148.6, 148.1, 147.8, 131.9, 131.7, 129.6, 129.5,123.2, 123.1, 122.1, 122.0, 118.6, 114.2, 112.9, 112.8, 111.4, 110.9,110.9, 110.7, 110.7, 91.8, 64.5, 56.0, 5 5.9, 14.6; HPLC (WatersNova-Pak/C,8 column, 3.9×150 mm, 4 micron, 1 mL/min, 45/55acrylonitrile/0.1% aqueous phosphoric acid 7 min, 100%; Anal. Calcd forC₂₀H₂₁NO₄. Theoretical: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.62; H,6.2 1; N, 4.07.

EXAMPLE 3 3-(3,4-Dimethoxyphenyl)-3-phenylacetate

[0072] A. 3,4-Dimethoxybenzophenone

[0073] 3,4-Dimethoxybenzophenone was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (2 mL, 15 mmol),aluminum chloride (2.2 g, 16.5 mmol) and benzoyl chloride (1.8 mL, 15.5mmol). The crude mixture was purified by flash column chromatography(silica gel, 3% ethyl acetate/methylene chloride) to yield 3.44 g (93%)of the product as a white solid: mp 99-100° C.; ¹H NMR (CDCl₃) δ7.82-7.30 (m, 7 H), 6.95-6.85 (m, 1H), 3.96 (s, 3H), 3.94 (s, 3H); ¹³CNMR (CDCl₃) δ 195.5, 153.0, 149.0, 138.2, 131.8, 130.2, 129.6, 128.1,125.4, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C₁₅H₁₄O₃. Theoretical:C, 74.36; H, 5.82. Found: C, 74.21; H, 6.01.

[0074] B. 3-(3,4-Dimethoxyphenyl)-3-phenylacetate (E and Z Isomers)

[0075] 3-(3,4-Dimethoxyphenyl)-3-phenylacetate was prepared analogouslyto 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxybenzophenone(4.8 g, 20 mmol), trimethylphosphonoacetate (4.1 g, 22 mmol) and lithiumhexamethyldisilazide (22 mL, 22 mmol, 1M) with a reaction time of 138hours at reflux. The crude mixture was purified by flash columnchromatography (silica gel, 1% ethyl acetate/methylene chloride) toafford 14.39 g (73%) of a mixture of the E and Z isomers as an oil. Theisomers were separated by additional purification (silica gel, 1% ethylacetate/methylene chloride) to afford pure samples of each of theisomers.

[0076] Isomer 1: ¹H NMR (CDCl₃) δ 7.40-7.36 (m, 3H), 7.26-7.20 (m, 2H),6.88 (s, 1H), 6.80 (s, 2H), 6.30 (s, 1H), 3.88 (s, 3H), 3.82 (s, 3H),3.60 (s, 3H); ¹³C NMR (CDCl₃) δ 166.5, 156.9, 150.4, 148.7, 138.9,133.4, 129.1, 128.1, 128.0, 127.8, 122.1, 114.9, 110.8, 110.6, 55.9,55.8, 51.1; Anal. Calcd for C₁₈H₁₈O₄. Theoretical: C, 72.47; H, 6.08.Found: C, 72.08; H, 6.11.

[0077] Isomer 2: ¹H NMR (CDCl₃) δ 7.35-7.32 (m, 5H), 6.90-6.83 (m, 2H),6.73 (s, 1H), 6.30 (s, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.64 (s, 3H);¹³C NMR (CDCl₃) δ 166.6, 156.7, 149.2, 148.3, 141.2, 131.1, 129.4,128.5, 128.3, 122.4, 116.4, 112.7, 110.4, 55.8, 55.7, 51.2; Anal. Calcdfor C₁₈H₁₈O₄. Theoretical: C, 72.47; H, 6.08. Found: C, 72.28; H, 5.94.

EXAMPLE 4 3-Phenyl-3-(3′-ethoxy-4-methoxyphenyl)acrylamide (E and ZIsomers)

[0078] The acrylamide was prepared analogously to3,3-bis-(3,4-dimethoxyphenyl)acrylate using3-ethoxy-4-methoxybenzophenone (0.3 g, 1.2 mmol),diethylcarbamoylmethylphosphonate (0.25 g, 1.3 mmol) and lithiumhexamethyldisilazide (1 mL, 1.3 mmol, 1.3M) with a reaction time of 54hours at reflux. The crude mixture was purified by flash columnchromatography (silica gel, 45% ethyl acetate/methylene chloride) toafford 0.06 g (17%) of a mixture of the E and Z isomers as an oil: ¹HNMR (CDCl₃) δ 7.54-7.19 (m, 10H), 7.00-6.65 (m, 6H), 6.34 (s, 2H), 5.54(s, 1H), 5.55 (s, 1H), 5.24 (s, 1H), 5.04 (s, 1H), 4.16 (m, 4H), 3.92(s, 3H), 3.87 (s, 3H), 1.60-1.33 (m, 6H), ¹³C NMR (CDCl₃) δ 168.7,168.6, 150.8, 150.4, 149.7, 148.4, 148.0, 140.7, 138.2, 133.0, 130.2,129.2, 129.1, 128.8, 128.3, 128.0, 121.9, 121.6, 120.0, 113.7, 111.9,111.4, 110.8, 64.4, 64.3, 55.9, 14.6; Anal. Calcd for C₁₈H₁₉NO₃0.35H₂O.Theoretical: C, 71.19; H, 6.54; N, 4.61. Found: C, 71.19; H, 6.68; N,4.45.

EXAMPLE 5 1-(3,4-Dimethoxyphenyl)-1-phenylprop-1-ene (E and Z Isomers)

[0079] 1-(3,4-Dimethoxyphenyl)-1-phenylprop-1-ene was preparedanalogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using3,4-dimethoxybenzophenone (3 g, 12.4 mmol), (ethyl)triphenylphosphoniumbromide (5.1 g, 13.6 mmol) and lithium hexamethyldisilazide (13.6 mL,13.6 mmol, 1M) with a reaction time of 4 hours at room temperature. Thecrude mixture was purified by flash column chromatography (silica gel,10% hexane/methylene chloride) to afford 1.3 g (41%) of a mixture of theE add Z isomers as a white solid: mp 72-73° C.; ¹H NMR (CDCl₃) δ7.40-6.80 (m, 16H), 6.16-6.08 (m, 2H), 3.90-3.80 (m, 12H), 1.97-1.73 (m,6H); ¹³C NMR (CDCl₃) δ 148.6, 148.5, 148.1, 147.8, 142.9, 142.3, 142.0,140.0, 136.0, 132.5, 129.9, 128.0, 128.0, 127.1, 126.7, 126.6, 123.8,122.6, 122.5, 119.8, 113.6, 110.8, 110.7, 110.4, 55.8, 55.8, 55.7, 15.7,15.5; Anal. Calcd for C₁₇H₁₈O₂. Theoretical: C, 80.28; H, 7.13. Found:C, 79.94; H, 7.12.

EXAMPLE 6 1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)prop-1-ene(E and Z Isomers)

[0080] 1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)prop-1-enewas prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylateusing 3,4-dimethoxy-3′-ethoxy-4′-methoxybenzophenone (1.6 g, 5 mmol),(ethyl)triphenylphosphonium bromide (2.04 g, 5.5 mmol) and lithiumhexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24hours at room temperature. The crude mixture was purified by flashcolumn chromatography (silica gel, 10% hexane/methylene chloride) toafford 0.8 g (49%) of a mixture of the E and Z isomers as a white solid:mp 65.5-68° C.; ¹H NMR (CDCl₃) δ 6.95-6.65 (m, 12H), 6.14-6.00 (m, 2H),4.11-3.78 (m, 22H), 1.86-1.74 (m, 6H), 1.50-1.36 (m, 6H); ¹³C NMR(CDCl₃) δ 148.5, 148.4, 148.1, 147.7, 141.8, 141.7, 136.1, 136.0, 132.6,132.5, 122.5, 122.3, 119.7, 114.7, 113.1, 111.9, 111.0, 110.7, 110.4,55.9, 55.8, 55.8, 55.7, 15.7, 14.7; Anal. Calcd for C₂₀H₂₄O₄.Theoretical C, 73.15; H, 7.37. Found: C, 73.33; H, 7.39.

EXAMPLE 7 1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)but-1-ene(E and Z Isomers)

[0081] 1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)but-1-ene wasprepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylateusing 3,4-dimethoxy-3′-ethoxy-4′-methoxybenzophenone (1 g, 3.2 mmol),propyltriphenylphosphonium bromide (1.34 g, 3.5 mmol) and lithiumhexamethyldisilazide (2.7 mL, 3.5 mmol, 1.3M) with a reaction time of2.5 hours at room temperature. The crude mixture was purified bychromatography (silica gel, methylene chloride) followed by a Kugelrohrdistillation to yield 0.77 g (71%) of a mixture of the E and Z isomersas an oil: ¹H NMR (CDCl₃) δ 6.92-6.65 (m, 12H), 6.02-5.89 (m, 2H),4.12-3.96 (m, 4H), 3.92 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 3.85 (s,3H), 3.82 (s, 3H), 3.81 (s, 3H), 2.22-2.04 (m, 4H), 1.51-1.38 (m, 6H),1.14-0.98 (m, 6H); ¹³C NMR (CDCl₃) δ 148.5, 148.1, 147.8, 147:7, 140.4,140.4, 136.0, 135.9, 133.0, 132.9, 130.1, 130.0, 122.2, 119.8, 114.6,113.1, 112.0, 111.0, 110.7, 110.4, 64.3, 64.2, 55.9, 23.2, 14.8, 14.7;Anal. Calcd for C₂₁H₂₆O₄. Theoretical: C, 73.66; H, 7.65. Found: C,73.32; H, 7.26.

EXAMPLE 8 3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile (E and ZIsomers)

[0082] 3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile was preparedanalogously to 3,3-bis-(3,4-dimethoxyphenyl)acrylate using3-ethoxy-4-methoxybenzophenone (1.3 g, 5 mmol),diethylcyanomethylphosphonate (0.9 mL, 5.5 mmol) and lithiumhexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24hours at room temperature. The crude mixture was purified by flashcolumn chromatography (silica gel, methylene chloride) to afford 1.35 g(96%) of a mixture of the E and Z isomers as a white solid: mp 74-77°C.; ¹HNMR (CDCl₃) δ 7.50-7.24 (m, 10H), 7.07-6.75 (m, 6H), 5.67 (s, 1H),5.60 (s, 1H), 4.15-3.95 (m, 4H), 3.92 (s, 3H), 3.89 (s, 3H), 1.50-1.36(m, 6H); ¹³C NMR (CDCl₃) δ 162.8, 162.7, 151.4, 150.9, 148.1, 147.1,147.9, 139.3, 137.1, 131.3, 130.2, 129.9, 129.5, 129.3, 128.6, 128.5,128.4, 123.1, 122.0, 118.3, 118.2, 113.9, 112.5, 110.9, 93.3, 92.9,64.4, 55.9, 55.9, 14.6; Anal. Calcd for C₁₈H₁₇NO₂. Theoretical C, 77.40;H, 6.13; N, 5.01. Found: C, 77.14; H, 6.06; N, 4 75.

EXAMPLE 9 3-(3-Ethoxy-4-methoxyphenyl)-3-phenylpropionitrile

[0083] To a solution of3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile (0.9 g, 3.2 mmol) ina mixture of ethanol and ethyl acetate (20 mL/30 mL) was added 0.5 g of10% palladium on carbon catalyst in portions. The mixture washydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 12days. The reaction mixture was filtered through celite and the filtratewas concentrated in vacuo to afford the crude product. The crude productwas purified by flash column chromatography (silica gel, 4%hexane/methylene chloride) to afford 0.15 g (15%) of the product as anoil: ¹H NMR (CDCl₃) δ 7.40-7.16 (m, 5H); 6.88-6.78 (m, 3H), 4.32 (t,J=7.5 Hz, 1H), 4.03 (q, J=7 Hz, 2H), 3.85 (s, 3H), 3.00 (d, J=7.5 Hz,2H), 1.42 (t, J=7 Hz, 3H); ¹³C NMR (CDCl₃) δ 148.7, 148.5, 141.5, 133.7,128.8, 127.4, 127.3, 119.5, 118.5, 112.7, 111.6, 64.4, 55.9, 46.7, 24.5,14.7; Anal. Calcd for C₁₈H₁₇NO₂. Theoretical: C, 76.84; H, 6.81; N,4.98. Found: C, 76.53; H, 6.92; N, 4.95.

EXAMPLE 103-(3,4-Dimethoxyphenyl)-3-(3′,5′-dimethoxyphenyl)-acrylonitrile (E and ZIsomers)

[0084] A. 3,4,3′,5′-Tetramethoxybenzophenone

[0085] 3,4,3′,5′-Tetramethoxybenzophenone was prepared analogously to4-(3,4-dimethoxybenzoyl)pyridine using butyl lithium (9 mL, 22 mmol,2.5M), 4-bromoveratrole (2.9 mL, 20 mmol) and 3,5-dimethoxybenzonitrile(3.75 g, 23 mmol). The crude product was purified by flash columnchromatography (silica gel, methylene chloride) to afford 1.54 g (26%)of the product: mp 107-110° C.; ¹H NMR (CDCl₃) δ 7.53-7.39 (m, 2H),6.95-6.84 (m, 3H), 6.70-6.60 (m, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.83(s, 6H); ¹³C NMR (CDCl₃) δ 195.0, 160.4, 153.0, 148.9, 140.1, 130.0,125.4, 112 0, 109.7, 107.5, 104.1, 56.0, 55.5; Anal. Calcd for C₁₇H₁₈O₅.Theoretical: C, 67.54; H, 6.00. Found: C, 67.38; H, 5.96.

[0086] B.3-(3,4-Dimethoxyplienyl)-3-(3′,5′-dimethoxyphenyl)acrylonitrile

[0087] 3-(3,4-Dimethoxyphenyl)-3-(3′,5′-dimethoxyphenyl)acrylonitrilewas prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylateusing 3,4,3′,5′-tetramethoxybenzophenone (0.7 g, 2.3 mmol),diethylcyanomethylphosphonate (0.42 mL, 2.5 mmol) and lithiumhexamethyldisilazide (1.9 mL, 2.5 mmol, 1.3M) with a reaction time of 60hours at room temperature. The crude product was purified by flashchromatography (silica gel, 1% ethyl acetate/methylene chloride) toafford 0.66 g (81%) of a mixture of the E and Z isomers as a whitesolid; mp 88-90° C.; ¹H NMR (CDCl₃) δ 7.10-6.80 (m, 6H), 6.61-6.40 (m,6H), 5.66 (s, 1H), 5.61 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.87 (s,3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.77 (s, 6H); ¹³C NMR (CDCl₃) δ 162.7,162.5, 160.7, 160.6, 151.1, 150.6, 148.8, 148.5, 141.3, 138.9, 131.1,129.2, 123.2, 122.1, 118.2, 118.0, 112.6, 110.9, 110.7, 110.7, 107.6,107.0, 102.1, 102.0, 93.4, 93.1, 56.0, 55.9, 55.5, 55.4; Anal. Calcd forC₁₉H₁₉NO₄. Theoretical: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.33; H,5.89; N, 4.03.

EXAMPLE 11 3-(3,4-Dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile

[0088] A. 3,4-Dimethoxy-3′-nitrobenzophenone

[0089] To a stirred ice bath cooled solution of veratrole (2.55 mL, 20mmol) in methylene chloride (30 mL) under nitrogen was added aluminumchloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resultingmixture was added 3-nitrobenzoyl chloride (3.8 g, 20 mmol) in 30 mL ofmethylene chloride. The reaction was then allowed to warm to roomtemperature and followed by heating to refluxed. After 5 hours at refluxthe reaction mixture was allowed to cool to room temperature and stirredfor 72 hours. The reaction mixture was then poured into 100 mL of icedwater and stirred for 20 minutes. This mixture was extracted with CH₂Cl₂(3×60 mL). The organic layer was dried over magnesium sulfate andconcentrated in vacuo to afford the crude product as a green solid. Thecrude product was purified by flash column chromatography (silica gel,CH₂Cl₂) to afford 2.21 g (39%) of the product as a yellow solid: mp133-135° C.; ¹H NMR (CDCl₃) 6 8.64-8.56 (m, 1H), 8.49-8.39 (m, 1H),8.10-8.05 (m, 1H), 7.76-7.65 (m, 1H), 7.55-7.47 (m, 1H), 7.36-7.29 (m,1H), 7.00-6.87 (m, 1H), 3.99 (s, 3H), 3.97 (s, 3H); ¹³C NMR (CDCl₃) δ192.8, 153.8, 149.4, 147.9, 139.7, 135.2, 129.5, 128.9, 126.2, 125.6,124.4, 11.8, 110.0, 56.2, 56.1; Anal. Calcd for C₁₅H₁₃NO₅. Theoretical:C, 62.72; H, 4.56; N, 4.88. Found: C, 62.74; H, 4.59; N, 4.89.

[0090] B. 3-(3,4-Dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile

[0091] 3-(3 ,4-Dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile wasprepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylateusing 3,4-dimethoxy-3′nitrobenzophenone (1.44 g, 5 mmol),diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithiumhexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24hours at room temperature. The crude product was purified by flashchromatography (silica gel, 3% hexane/methylene chloride) to afford 1.12g (72%) of a mixture of the E and Z isomers as a yellow solid: mp117.5-120° C.; ¹H NMR (CDCl₃) δ 8.40-8 17 (m, 4H), 7.90-7.55 (m, 4H),7.08-6.89 (in, 6H), 5.84 (s, 1H), 5.71 (s, 1H), 3.95 (s, 3H),3.92 (s,3H), 3.88 (s, 3H), 3.85 (s, 3H); ¹³CNMR (CDCl₃) δ 160.2, 160.1, 151.7,151.1, 149.2, 148.3, 148.2, 141.0, 138.8, 135.4, 134.4, 129.9, 129.7,129.7, 128.1, 124.8, 124.6, 124.4, 123.3, 123.1, 122.3, 117.4, 117.3,112.3, 111.0, 110.4, 95.7, 94.8, 56.0, 55.9; Anal. Calcd for C₁₇H₁₄N₂O₄.Theoretical: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.57; H, 4.64; N,8.92.

EXAMPLE 12 3-(3′-Aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile (Eand Z Isomers)

[0092] To a solution of3-(3,4-dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile (0.7 g, 2.3mmol) in 40 mL of ethyl acetate was added 0.1 g of 10% palladium oncarbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatusat 55-60 psi of hydrogen for 2.5 hours. The reaction mixture wasfiltered through celite and the filtrate was concentrated in vacuo toafford the crude product. The crude product was purified by flash columnchromatography (silica gel, 15% ethyl acetate/methylene chloride) toafford 0.25 g (56%) of a mixture of the E and Z isomers as a yellowsolid: mp 100-101° C.; ¹H NMR (CDCl₃) δ 7.30-6.59 (m, 14H); 5.63 (s,1H), 5.59 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.84 (s,3H); ¹³C NMR (CDCl₃) δ 163.1, 162.9, 151.1, 150.5, 148.8, 148.7, 146.5,146.4, 140.4, 138.2, 131.5, 129.5, 129.5, 129.4, 123.2, 122.1, 119.9,119.0, 118.4, 118.2, 116.8, 116.6, 115.9, 115.0, 112.7, 111.0, 110.7,93.3, 92.7, 56.1, 56.0, 55.9; Anal. Calcd for C₁₇H₁₆N₂O₃. Theoretical:C, 72.84; H, 5.75; N, 9.99. Found: C, 72.48; H, 6.05; N, 9.58.

EXAMPLE 13 3,4-Dimethoxy-3′-aminobenzophenone

[0093] To a solution of 3,4-dimethoxy-3′-nitrobenzophenone (0.5 g, 1.7mmol) in 40 mL of ethyl acetate was added 0.05 g of 10% palladium oncarbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatusat 55-60 psi of hydrogen for 1.5 hours. The reaction mixture wasfiltered through celite and the filtrate was concentrated in vacuo toafford the crude product. The crude product was purified by flash columnchromatography (silica gel, 10% ethyl acetate/methylene chloride) toafford 0.17 g (38%) of the product as a yellow solid: mp 157-175° C.; ¹HNMR (CDCl₃) δ 7.56-6.80 (m, 7H); 3.95 (s, 3H), 3.94 (s, 3H); ¹³C NMR(CDCl₃) δ 195.7, 152.9, 148.9, 146.4, 139.3, 130.3, 128.9, 125.4, 120.1,118.4, 115.6, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C₁₅H₁₅NO₃.Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.00; H, 6.10; N,5.13.

EXAMPLE 14 3-(3,4-Dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile (E andZ Isomers)

[0094] A. 3,4-Dimethoxy-4′-nitrobenzophenone

[0095] 3,4-Dimethoxy-4′-nitrobenzophenone was prepared analogously to3,4-dimethoxy-3′-nitrobenzophenone using veratrole (3.8 mL, 30 mmol),aluminum chloride (4.4 g, 33 inmol) and 4-nitrobenzoyl chloride (5.7 g,30 mmol) with a reaction time of 48 hours at reflux. The crude mixturewas purified by flash column chromatography (silica gel, 4% ethylacetate/methylene chloride) to afford 1.69 g (78%) of the product as awhite solid: mp 172-173° C.; ¹H NMR (CDCl₃) δ 8.43-8.31 (m, 2H),7.97-7.86 (m, 2H), 7.55-7.46 (m, 1H), 7.40-7.30 (m, 1H), 7.00-6.89 (m,1H), 3.99 (s, 3H), 3.96 (s, 3H); ¹³C NMR (CDCl₃) δ 193.4, 153.8, 149.4,149.3, 143.8, 130.2, 130.0, 125.8, 123.4, 111.7, 109.9, 56.1, 56.0;Anal. Calcd for C₁₅H₁₃NO₅. Theoretical: C, 62.72; H, 4.56; N, 4.88.Found: C, 62.49; H, 4.68; N, 4.86.

[0096] B. 3-(3,4-Dimethoxyphenyl)-3-(4′-nitrophenyl)acrylonitrile

[0097] 3-(3,4-Dimethoxyphenyl)-3-(4′-nitrophenyl)acrylonitrile wasprepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylateusing 3,4-dimethoxy-4′nitrobenzophenone (4 g, 14 mmol),diethylcyanomethylphosphonate (2.5 mL, 15.4 mmol) and lithiumhexamethyldisilazide (11.8 mL, 15.4 mmol, 1.3M) with a reaction time of17 hours at room temperature. The crude product was purified bychromatography (silica gel, 3% hexane/methylene chloride) to afford 2.38g (55%) of a mixture of the E and Z isomers as a yellow solid: mp117.5-120° C.; ¹H NMR (CDCl₃) δ 8.40-8.20 (m, 4H), 7.70-7.46 (m, 4H),7.06-6.75 (m, 6H), 5.84 (s, 1H), 5.70 (s, 1H), 3.95 (s, 3H), 3.93 (s,3H), 3.88 (s, 3H), 3.85 (s, 3H); ¹³C NMR (CDCl₃) δ 160.3, 151.7, 151.1,149.2, 148.9, 148.7, 148.5, 148.5, 143.5, 130.6, 129.9, 129.6, 128.2,123.7, 123.1, 122.2, 117.4, 117.3, 112.3, 111.0, 110.5, 96.2, 94.9,56.0, 56.0; Anal. Calcd for C₁₇H₁₄N₂O₄. Theoretical: C, 65.80; H, 4.55;N, 9.03. Found: C, 65.45; H, 4.66; N, 8.82.

EXAMPLE 15 3-(4-Aminophenyl)-3-(3,4-dimetlioxyphenyl)acrylonitrile

[0098] 3-(4-Aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile wasprepared analogously to3-(3,4-dimethoxyphenyl)-3-(3-aminophenyl)acrylonitrile using3-(3,4-dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile (1.24 g, 4 mmol)and 0.15 g of 10% palladium on carbon catalyst in 100 mL of ethylacetate. The crude mixture was purified by flash column chromatography(silica gel, 5% ethyl acetate/methylene chloride) to afford 0.19 g (17%)of a mixture of the E and Z isomers as a yellow solid: mp 150-152° C.;¹H NMR (CDCl₃) o 7.38-6.56 (m, 14H); 5.51 (s, 1H), 5.44 (s, I H), 3.97(br s, 4H), 3.93 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H); ¹³CNMR (CDCl₃) δ 162.8, 162.6, 150.8, 150.3, 148.8, 148.7, 148.5, 148.4,132.4, 131.4, 130.1, 129.5, 129.9, 128.6, 126.7, 123.0, 122.1, 114.4,114.3, 112.8, 111.6, 110.7, 90.3, 89.9, 56.0, 55.9; Anal. Calcd forC₁₇H₁₆N₂O₃. Theoretical: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.79; H,5.83; N, 9.59.

EXAMPLE 16 3,4-Dimethoxy-4′-aminobenzophenone

[0099] 3,4-Dimethoxy-4′-aminobenzophenone was prepared analogously to3,4-dimethoxy-3′-aminobenzophenone using3,4-dimethoxy-4′-nitrobenzophenone (1 g, 3.5 mmol) and 0.1 g of 10%palladium on carbon catalyst in 110 mL of ethyl acetate. The crudeproduct was purified by flash column chromatography (silica gel, 12%ethyl acetate/methylene chloride) to afford 0.32 g (36%) of the productas a yellow solid: mp 189-191° C.; ¹H NMR (CDCl₃) δ 7.80-7.62 (m, 2H);7.45-7.29 (m, 2H), 6.96-6.80 (m, 1H), 6.75-6.61 (m, 2H), 4.14 (s, 2H),3.95 (s, 3H), 3.93 (s, 3H); ¹³C NMR (CDCl₃) δ 194.2, 152.2, 150.5,148.8, 132.6, 131.3, 128.0, 124.3, 113.6, 112.3, 109.7, 56.0, Anal.Calcd for C₁₅H₁₅NO₃. Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C,69.95; H, 6.18; N, 5.13.

EXAMPLE 17 3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile

[0100] A. 3,4-Dimethoxy-4′-methylbenzophenone

[0101] The title compound was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (3.9 mL, 28 mmol),aluminum chloride (4.1 g, 31 mmol) and 4-methylbenzoyl chloride (4.6 mL,29 mmol) with a reaction time of 6 hours at room temperature. The crudemixture was purified by flash column chromatography (silica gel, 2%ethyl acetate/methylene chloride) to afford 4.22 g (59%) of the productas a white solid: mp 121.5-122° C.; ¹H NMR (CDCl₃) δ 7.70-7.67 (d, J=8Hz, 2H), 7.48-7.26 (m, 4H), 6.91-6.88 (d, J=8.3 Hz, 1H), 6.96 (s, 3H),3.94 (s, 3H), 2.44 (s, 3H); ¹³C NMR (CDCl₃) δ 195.1, 152.6, 148 8,142.4, 135.3, 130.3, 129.8, 128.7, 125.0, 112.0, 109.6, 55.9, 55.8,21.4; Anal. Calcd for C₁₆H₁₆O₃. Theoretical: C, 74.98, H, 6.29. Found:C, 74.84; H, 6.43.

[0102] B. 3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile

[0103] 3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile wasprepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylateusing 3,4-dimethoxy-4′-methylbenzophenone (2.3 g, 9 mmol),diethylcyanomethylphosphonate (1.8 nmL, 9.9 mmol) and lithiumhexamethyldisilazide (10 mL, 9.9 mmol, 1M) with a reaction time of 22hours at room temperature. The crude product was purified bychromatography (silica gel, 1% ethyl acetate/methylene chloride) toafford 1.83 g (73%) of a mixture of the E and Z isomers as a whitesolid: mp 83.5-86.5° C.; ¹H NMR (CDCl₃) δ 7.35-7.20 (m, 8H), 7.04-6.81(m, 6H), 5.62 (s, 1H), 5.59 (s, 1H), 3.90 (s, 3H), 3.90 (s, 3H), 3.88(s, 3H), 3.82 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3H); ¹³C NMR (CDCl₃) δ162.7, 162.6, 160.0, 150.4, 148.8, 148.5, 140.6, 140.1, 136.3, 134.1,131.6, 129.5, 129.2, 129.0, 128.5, 123.0, 122.1, 118.4, 118.3, 112.6,111.1, 110.7, 92.6, 92.4, 55.9, 55.9, 55.8, 21.3, 21.2; Anal. Calcd forC₁₈H₁₇NO₂. Theoretical: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.64; H,5.93; N, 5.01.

EXAMPLE 18 3-(4-Biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

[0104] A. 3,4-Dimethoxy-4′-phenylbenzophenone

[0105] 3,4-Dimethoxy-4′-phenylbenzophenone was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (2.4 g, 17 mmol),aluminum chloride (2.5 g, 19 mmol) and 4-biphenylcarbonyl chloride (4 g,18 mmol) with a reaction time of 24 hours at room temperature. The crudeproduct was purified by flash column chromatography (silica gel, 2%ethyl acetate/methylene chloride) to afford 3.86 g (70%) of the productas a white solid: mp 103-104° C.; ¹H NMR (CDCl₃) δ 7.88-7.84 (m, 2H),7.73-7.64 (m, 4H), 7.52-7.40 (m, 5H), 6.93-6.90 (m, 1H), 3.97 (s, 3H),3.96 (s, 3H); ¹³C NMR (CDCl₃) δ 194.9, 152.9, 148.9, 144.5, 139.8,136.8, 130.2, 130.2, 128.8, 127.9, 127.1, 126.7, 125.2, 112.0, 109.7,55.9, 55.9; Anal. Calcd for C₂₁H₁₈O₃. Theoretical: C, 79.23; H, 5.70.Found: C, 78.91; H, 5.87.

[0106] B. 3-(4-Biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

[0107] 3-(4-Biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile wasprepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylateusing 3,4-dimethoxy-4′-phenylbenzophenone (2.33 g, 7.32 mmol),diethylcyanomethylphosphonate (1.5 ML, 8.1 mmol) and lithiumhexamethyldisilazide (8.1 mL, 8.1 mmol, 1M) with a reaction time of 22hours. The crude product was purified by chromatography (silica gel, 1%ethyl acetate/methylene chloride) to. afford 1.76 g (70%) of a mixtureof the E and Z isomers as a white solid: mp 132.0-134° C.; ¹H NMR(CDCl₃) δ 7.70-7.39 (m, 18H), 7.10-6.80 (m, 6H), 5.69 (s, 1H), 5.68 (s,1H), 3.95 (s, 6H), 3.93 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H); ¹³C NMR(CDCl₃) δ 162.2, 151.1, 148.8, 148.6, 143.0, 142.6, 140.0, 137.9, 135.9,131.4, 130.1, 129.3, 129.1, 128.8, 128.8, 127.9, 127.1, 127.0, 126.0,126.9, 123.1, 122.2, 118.3, 118.2, 112.6, 111.1, 110.7, 93.2, 92.9,56.0, 55.9, 55.8; Anal. Calcd for C₂₃H₁₉NO₂. Theoretical: C, 80.92; H,5.61; N, 4.10. Found: C, 80.55; H, 5.80; N, 3.95.

EXAMPLE 19 3-(3,4-Dimethoxyphenyl)-3-(4′-fluorophenyl)acrylonitrile

[0108] 3-(3,4-Dimethoxyphenyl)-3-(4′-fluorophenyl)acrylonitrile wasprepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylateusing 3,4-dimethoxy-4′-fluorobenzophenone (1.3 g, 5 mmol),diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithiumhexamethyldisilazide (5.5 mL, 5.5 mmol, 1M) with a reaction time of 22hours at room temperature. The crude product was purified bychromatography (silica gel, 1% ethyl acetate/methylene chloride) toafford 2.38 g (55%) of a mixture of the E and Z isomers as a whitesolid: mp 100-102° C.; ¹H NMR (CDCl₃) δ 7.54-6.74 (m, 14H), 5.67 (s,1H), 5.57 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (s,3H); ¹³C NMR (CDCl₃) δ 166.0, 165.6, 162.0, 161.6, 151.3, 150.7, 148.9,148.7, 135.4, 135.4, 133.2, 133.1, 131.7, 131.6, 131.3, 130.7, 130.5,129.2, 123.1, 122.1, 118.1, 118.0, 115.8, 115.8, 115.5, 115.4, 112.6,111.0, 110.8, 93.4, 93.2, 56.0, 56.0, 55.9; Anal. Calcd for C₁₇H₁₄FNO₂.Theoretical: C, 72.07; H, 4.98; N, 4.94. Found: C, 71.91; H, 4.98; N,4.79.

EXAMPLE 20 3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylonitrile (E and ZIsomers)

[0109] A. 2-(3,4-Dimethoxybenzoyl)naphthalene

[0110] 2-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (2.6 mL, 20 mmol),aluminum chloride (2.9 g, 22 mmol) and 2-naphthoyl chloride (3.9 g, 20mmol) with a reaction time of 4 hours at reflux. The crude product waspurified by flash column chromatography (silica gel, 2.5% ethylacetate/methylene chloride) to afford 4.52 g (77%) of the product as awhite solid: mp 120-121.5° C.; ¹H NMR (CDCl₃) δ 8.24 (s, 1H), 8.03-7.84(m, 4H), 7.68-7.40 (m, 4H), 7.00-6.87 (m, 1H), 3.97 (s, 3H), 3.95 (s,3H); ¹³C NMR (CDCl₃) δ 195.5, 153.0, 149.0, 135.5, 134.9, 132.2, 131.0,130.4, 129.2, 128.1, 128.0, 127.8, 126.7, 1259, 125.4, 112 2, 109.8,56.1, 56.0; Anal. Calcd for C₁₉H₁₆O₃. Theoretical: C, 78.06; H, 5.52.Found: C, 77.73; H, 5.69.

[0111] B. 3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylonitrile

[0112] 3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylonitrile was preparedanalogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using2-(3,4-dimethoxybenzoyl)naphthalene (2.9 g, 10 mmol),diethylcyanomethylphosphonate (1.8 mL, 11 mmol) and lithiumhexamethyldisilazide (8.5 mL, 11 mmol, 1.3M) with a reaction time of 1hour at reflux. The crude product was purified by chromatography (silicagel, methylene chloride) to afford 2.93 g (93%) of a mixture of the Eand Z isomers as a white solid: mp 121-123° C.; ¹H NMR (CDCl₃) δ8.11-6.78 (m, 20H), 5.76 (s, 1H), 5.75 (s, 1H), 3.96 (s, 3H), 3.92 (s,3H), 3.85 (s, 3H), 3.80 (s, 3H); ¹³C NMR (CDCl₃) δ 162.7, 162.7, 151.2,150.6, 148.9, 148.7, 136.6, 134.5, 134.0, 133.8, 132.8, 131.5, 129.7,129.4, 129.0, 128.6, 128.6, 128.3, 128.1, 127.7, 127.7, 127.4, 127.2,126.8, 126.6, 125.4, 123.2, 122.2, 118.4, 118.2, 112.7, 111.1, 110.8,93.9, 93.4, 56.0, 56.0, 55.9; Anal. Calcd for C₂₁H₁₇NO₂. Theoretical: C,79.98; H, 5.43; N, 4.44. Found: C, 79.90; H, 5.65; N, 4.46.

EXAMPLE 21 3-(3,4-Dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile (E and Z Isomers)

[0113] A. 1-(3,4-Dimethoxybenzoyl)-3,4-methylenedioxybenzene

[0114] 1-(3,4-Dimethoxybenzoyl)-3,4-methylenedioxybenzene was preparedanalogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3mL, 10 mmol), aluminum chloride (1.5 g, 11 mmol) and piperonyloylchloride (1.9 g, 10 mmol) with a reaction time of 2.5 hours at roomtemperature. The crude product was purified by flash columnchromatography (silica gel, 5% ethyl acetate/methylene chloride) toafford 1.99 g (69%) of the product as a white solid: mp 164-165° C.; ¹HNMR (CDCl₃) δ 7.46-7.26 (m, 4H), 6.95-6.82 (m, 2H), 6.06 (s, 2H), 3.96(s, 3H), 3.94 (s, 3H); ¹³C NMR (CDCl₃) δ193.9, 152.7, 151.0, 148.9,147.8, 132.4, 130.6, 126.1, 124.8, 112.2, 109.9, 109.7, 107.6, 101.7,56.0, 56.0; Anal. Calcd for C₁₆H₁₄O₅. Theoretical: C, 67.13; H, 4.93.Found: C, 66.86; H, 5.11.

[0115] B.3-(3,4-Dimethoxypbenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile3-(3,4-Dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile wasprepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylateusing 1-(3,4-dimethoxybenzoyl)-3,4-methylenedioxybenzene (1.43 g, 5mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithiumhexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 1hour at reflux and 24 hours at room temperature. The crude product waspurified by chromatography (silica gel, 2% ethyl acetate/methylenechloride) to afford 0.79 g (51%) of a mixture of the E and Z isomers asan off white solid: mp 121-123° C.; ¹H NMR (CDCl₃) δ 7.10-6.73 (m, 12H),6.13-5.94 (m, 4H), 5.57 (s, 1H), 5.53 (s, 1H), 3.94 (s, 3H), 3.92 (s,3H), 3.87 (s, 3H), 3.84 (s, 3H); ¹³C NMR (CDCl₃) δ 162.3, 151.0, 150.5,149.6, 149.1, 148.8, 148.5, 147.9, 133.2, 131.6, 130.8, 129.4, 124.3,123.5, 123.1, 122.1, 118.5, 118.3, 112.6, 111.1, 110.7, 109.9, 108.5,108.2, 101.6, 101.5, 92.2, 92.2, 56.0, 55.9, 55.9; Anal. Calcd forC₁₈H₁₅NO₄. Theoretical: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.61; H,5.01; N, 4.37.

EXAMPLE 22 3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile (E and ZIsomers)

[0116] A. 4-(3,4-Dimethoxybenzoyl)pyridine

[0117] A hexane solution of butyl lithium (9 mL, 22 mmol, 2.5M) wasslowly added to a stirring solution of 4-bromoveratrole (2.9 mL, 20mmol) in 40 mL of tetrahydrofuran under nitrogen at −70° C. After 15minutes a solution of 4-cyanopyridine in 12 mL of tetrahydrofuran wasadded to the reaction mixture and stirring was continued for 45 minutes.The reaction was then allowed to warm to −10° C. and the reaction wascarefully quenched with hydrochloric acid (45 mL, 1N). The mixture wasstirred for 30 minutes at room temperature. The pH was then adjusted to12 with 50 mL of a 10% aqueous solution of sodium hydroxide. The mixturewas extracted with ether (3×50 mL). The combined ethereal extracts werewashed with brine (100 mL) then dried over magnesium sulfate andconcentrated in vacuo to a brown solid The crude product was purified byflash column chromatography (silica gel, 3% methanol/methylene chloride)to afford after vacuum drying (60° C., 1 mm) 1.9 g (39%) of the product:mp 117-118° C.; ¹H NMR (CDCl₃) δ 8.85-8.76 (m, 2H), 7.60-7.50 (m, 3H),7.40-7.30 (m, 1H), 6 97-6.88 (m, 1H), 3.98 (s, 3H), 3.96 (s, 3H); ¹³CNMR (CDCl₃) δ 193.7, 153.9, 150.1, 149.3, 145.2, 128.7, 125.9, 122.6,111.5, 109.9, 56.1, 56.0; Anal. Calcd for C₁₄H₁₃NO₃. Theoretical: C,69.12; H, 5.39; N, 5.76. Found: C, 69.05; H. 5.39; N, 5.85.

[0118] B. 3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile was preparedanalogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using4-(3,4-dimethoxybenzoyl)pyridine (1 g, 4 mmol),diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithiumhexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 24hours at room temperature. The crude product was slurried in 10 mL ofhexane. The mixture was filtered, the solid was washed with hexane, airdried and then dried in vacuo to afford 0.91 g (85%) of a mixture of theE and Z isomers as an off white solid: mp 116-125° C.; ¹H NMR (CDCl₃) δ8.80-8.63 (m, 4H), 7.40-7.20 (m, 4H), 7.04-6.74 (m, 6H), 5.81 (s, 1H),5.70 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H);¹³C NMR (CDCl₃) δ 160.1, 157.0, 151.6, 151.1, 150.3, 149.2, 148.9,146.7, 144.9, 129.6, 127.8, 123.7, 123.1, 122.7, 122.1, 117.4, 117.1,112.3, 111.0, 110.5, 96.1, 94.8, 56.0, 56.0; Anal. Calcd for C₁₆H₁₄N₂O₂.Theoretical: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.35; H, 5.43; N,10.47.

EXAMPLE 23 3-(3,4-Dimethoxyphenyl)-3-pyridin-2-ylacrylonitrile

[0119] A. 2-(3,4-Dimethoxybenzoyl)pyridine

[0120] 2-(3,4-Dimethoxybenzoyl)pyridine was prepared analogously to4-(3,4-dimethoxybenzoyl)pyridine using 2-cyanopyridine. The crudemixture was purified by flash column chromatography (silica gel, 1%methanol/methylene chloride) to afford after drying in vacuo (60° C., 1mm) 1.67 g (34%) of the product: mp 91.5-93° C.; ¹H NMR (CDCl₃) δ8.76-8.70 (m, 1H), 8.05-7.71 (m, 4H), 7.55-7.45 (m, 1H), 7.00-6.89 (m,1H), 3.96 (s, 3H), 3.96 (s, 3H); ¹³C NMR (CDCl₃) δ 192.1, 155.7, 153.3,148.7, 148.2, 136.9, 128.9, 126.7, 125.7, 124.4, 112.6, 109.8, 56.0,55.9; Anal. Calcd for C₁₄H₁₃NO₃. Theoretical: C, 69.12; H, 5.39; N,5.76. Found: C, 68.96; H, 5.47; N, 5.66.

[0121] B. 3-(3,4-Dimethoxyphenyl)-3-pyridin-2-ylacrylonitrile

[0122] 3-(3,4-Dimethoxyphenyl)-3-pyridin-2-yl)acrylonitrile was preparedanalogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using2-(3,4-dimethoxybenzoyl)pyridine (1 g, 4 mmol),diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithiumhexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 17hours at room temperature. The crude product was purified by flashcolumn chromatography (silica gel, 1% methanol/methylene chloride) toafford 0.8 g (75%) of a mixture of the E and Z isomers as a brown solid.The isomers were separated by additional purification (silica gel, 10%ethyl acetate/methylene chloride) to afford pure samples of each of theisomers.

[0123] Isomer 1: mp 125-126° C.; ¹H NMR (CDCl₃) δ 8.75-8.65 (m, 1H),7.75-7.60 (m, 1H), 7.41-7.16 (m, 2H), 7.10-6.90 (m, 3H), 6.52 (s, I H),3.95 (s, 3H), 3.89 (s, 3H); ¹³C NMR (CDCl₃) δ 159.9, 154.9, 150.4,149.9, 148.9, 136.7, 128.0, 124.6, 124.1, 122.6, 118.1, 112.4, 111.1,97.8, 56.1, 56.0; Anal. Calcd for C₁₆H₁₄N₂O₂. Theoretical: C, 72 17; H,5.30; N, 10.52. Found: C, 71.90; H, 5.28; N, 10.33.

[0124] Isomer 2: mp 134.5-135.5° C.; ¹H NMR (CDCl₃) δ 8.82-8.70 (m, 1H),7.88-7.76 (m, 1H), 7.60-7.34 (m, 2H), 6.94-6.80 (m, 3H), 5.82 (s, 1H),3.91 (s, 3H), 3.83 (s, 3H); ¹³C NMR(CDCl₃)δ 160.8, 155.3, 151.2, 149.9,149.0, 136.6, 130.2, 124.9, 124.3, 122.1, 117.6, 110.9, 95.4, 56.0;Anal. Calcd for C₁₆H₁₄N₂O₂. Theoretical: C, 72.17; H, 5.30; N, 10.52.Found: C, 72.13; H, 5.23; N, 10.40.

EXAMPLE 24 3-(3,4-Dimethoxyphenyl)-3-(2-furyl)acrylonitrile (E and ZIsomers)

[0125] A. 2-(3,4-Dimethoxybenzoyl)furane

[0126] 2-(3,4-Dimethoxybenzoyl)furane was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol),aluminum chloride (1.5 g, 10 nmmol) and 2-furoyl chloride (1.1 mL, 10mmol) with a reaction time of 2 hours at reflux. The crude product waspurified by flash column chromatography (silica gel, 4% ethylacetate/methylene chloride) to afford 1.69 g (78%) of the product as awhite solid: mp 112-114° C.; ¹H NMR (CDCl₃) δ 7.78-7.66 (m, 2H),7.59-7.52 (m, 1H), 7.26-7.17 (m, 1H), 6.96-6.90 (m, 1H), 6.63-6.55 (m,1H), 3.97 (s, 3H), 3.96 (s, 3H); ¹³C NMR (CDCl₃) δ 180.9, 153.0, 152.5,148.9, 146.5, 129.8, 124.0, 119.6, 112.0, 111.7, 110.0, 56.0, 55.9;Anal. Calcd for C₁₃H₁₂O₄. Theoretical: C, 67.23; H, 5.21. Found: C,67.09; H, 5.21.

[0127] B. 3-(3,4-Dimethoxyphenyl)-3-(2-furyl)acrylonitrile

[0128] 3-(3,4-Dimethoxyphenyl)-3-(2-furyl)acrylonitrile was preparedanalogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using2-(3,4-dimethoxybenzoyl)flurane (0.87 g, 4 mmol),diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithiumhexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 3hours at room temperature. The crude product was purified bychromatography (silica gel, 2% ethyl acetate/methylene chloride) toafford 0.78 g (76%) of a mixture of the E and Z isomers as an off whitesolid: mp 78-82° C.; ¹H NMR (CDCl₃) δ 7.68-7.73 (m, 2H), 7.16-6.75 (m,7H), 6.54-6.39 (m, 3H), 5.87 (s, 1H), 5.30 (s, 1H), 3.93 (s, 3H), 3.93(s, 3H), 3.91 (s, 3H), 3.88 (s, 3H); ¹³C NMR (CDCl₃) δ 152.0, 150.7,150.5, 150.4, 149.3, 148.8, 148.7, 148.7, 145.2, 145.0, 129.6, 126.7,122.1, 121.6, 118.1, 118.0, 116.5, 115.6, 112.5, 112.1, 112.0, 111.5,110.9, 110.8, 90.5, 90.2, 55.9, 55.9, 55.9, 55.8; Anal. Calcd forC₁₅H₁₃NO₃. Theoretical: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.61; H,5.09; N, 5.18.

EXAMPLE 25 3-(3,4-Diethylphenyl)-3-phenylacrylonitrile (E and Z Isomers)

[0129] A. 3,4-Diethylbenzophenone

[0130] To a stirred ice bath cooled solution of diethylbenzene (1.7 mL,10 mmol) in methylene chloride (30 mL) under nitrogen was added aluminumchloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resultingreaction mixture was added benzoyl chloride (1.2 mL, 10 mmol). Thereaction mixture was allowed to warm to room temperature and was thenstirred at room temperature for 1.5 hours. The reaction mixture waspoured into 60 mL of iced water and stirred for 20 minutes. Theresulting mixture was extracted with methylene chloride (2×40 mL). Thecombined extracts were dried over magnesium sulfate and concentrated invacuo to afford the crude product as an orange oil. The crude productwas purified by flash column chromatography (silica gel, 2.5% ethylacetate/hexane) to afford 1.22 g (51%) of the product as a yellow oil:¹H NMR (CDCl₃) δ 7.85-7.41 (m, 7H), 7.30-7.20 (m, 1H) 2.83-2.61(m, 4H),1.35-1.17 (m, 6H); ¹³C NMR (CDCl₃) δ 196.8, 147.0, 141.9, 138.1, 135.3,132.1, 132.1, 130.1, 130.0, 128.1, 128.1, 25.6, 25.4, 15.1, 15.0; Anal.Calcd for C₁₇H₁₈O. Theoretical: C, 85.67; H, 7.61. Found: C, 85.38; H,7.42.

[0131] B. 3-(3,4-Diethylphenyl)-3-phenylacrylonitrile

[0132] 3-(3,4-Diethylphenyl)-3-phenylacrylonitrile was preparedanalogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using3,4-diethylbenzophenone (0.95 g, 4 mmol), diethylcyanomethylphosphonate(0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol,1.3M) with a reaction time of 2 hours at room temperature. The crudeproduct was purified by flash chromatography (silica gel, 8% ethylacetate/methylene chloride) to afford an oil which was stirred in hexaneuntil it solidified. The resulting slurry was filtered, the solid washedwith hexane, air dried and then dried in vacuo to afford 0.6 g (57%) ofa mixture of the E and Z isomers as a white solid: mp 63-64° C.; ¹H NMR(CDCl₃) δ 7.51-6.99 (m, 16H), 5.72 (s, 2H), 2.76-2.55 (m, 8H), 1.32-1.14(m, 12H); ¹³C NMR (CDCl₃) δ 163.3, 144.7, 142.2, 137.3, 136.5, 130.2,129.8, 129.6, 128.6, 128.5, 128.4, 128.3, 127 2, 126.2, 118.2, 93.9, 937, 25.5, 25 3, 15.2, 15 0.

EXAMPLE 26 3-(3,4-Diethylphenyl)-3(3,4-dimethoxyphenyl)acrylonitrile

[0133] A. 3′,4′-Diethyl-3,4-dimethoxybenzophenone

[0134] 3′,4′-Diethyl-3,4-dimethoxybenzophenone was prepared analogouslyto 3,4-diethylbenzophenone using diethylbenzene (2.5 mL, 15 mmol),aluminum chloride (2.2 g, 16.5 mmol) and 3,4-dimethoxybenzoyl chloride(3 g, 15 mmol) with a reaction time of 3 hours at reflux. The crudeproduct was purified by flash column chromatography (silica gel, 1.5%ethyl acetate/hexane) to afford 0.84g (20%) of the product as an orangesolid: mp 60-61° C.; ¹HNMR(CDCl₃) δ 7.74-7.15 (m, 5H), 7.00-6.80 (m, 1H)3.96 (s, 3H), 3.94 (s, 3H), 2.93-2.60 (m, 4H), 1.43-1.15 (m, 6H); ¹³CNMR (CDCl₃) δ 195.5, 152.7, 148.8, 146.3, 141.7, 135.9, 130.6, 129.8,128.0, 127.7, 125.1, 112.2, 109.7, 56.0, 25.6, 25.4, 15.1, 15.0; Anal.Calcd for C₁₉H₂₂O₃. Theoretical: C, 76.48; H, 7.43. Found: C, 76.53; H,7.34.

[0135] B. 3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

[0136] 3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile wasprepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylateusing 3′,4′-diethyl-3,4-dimethoxybenzophenone (0.51 g, 1.7 mmol),diethylcyanomethylphosphonate (0.31 mL, 1.9 mmol) and lithiumhexamethyldisilazide (1.4 mL, 1.9 mmol, 1.3M) with a reaction time of 60hours at room temperature. The crude product was purified bychromatography (silica gel, 1% ethyl acetate/methylene chloride) toafford an oil which was stirred in hexane until it solidified. Theresulting slurry was filtered, the solid washed with hexane, air dried,and dried in vacuo to afford 0.31 g (57%) of a mixture of the E and Zisomers as an off white solid: mp 78-82° C.; ¹H NMR (CDCl₃) δ 7.30-6.75(m, 12H), 5.61 (s, 1H), 5.60 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87(s, 3H), 3.83 (s, 3H), 2.80-2.59 (m, 8H), 1.35-1.14 (m, 12H); ¹³C NMR(CDCl₃) δ 163.0, 163.0, 151.0, 150.5, 148.8, 148.6, 144.6, 143.9, 142.1,141.8, 136.8, 134.5, 131.9, 129.7, 128.6, 128.5, 128.2, 127.3, 126.3,123.2, 122.2, 118.7, 118.6, 112.8, 111.3, 110.7, 92.5, 92.2, 56.1, 56.0,25.5, 25.4, 25 4, 25.3, 15.3, 15.2, 15.0, 14.9; Anal. Calcd forC₂₁H₂₃NO₂. Theoretical: C, 78.47; H, 7.21; N, 4.36. Found: C, 77.80; H,7.25; N, 4.68.

EXAMPLE 27 4-(3-Ethoxy-4-methoxyphenyl)-4-phenyl-3-butan-2-one

[0137] To a suspension of cuprous cyanide (0.21 g, 2.3 mmol) intetrahydrofuran (8 mL) at −70° C. under nitrogen was added acyclohexyl/ether solution of phenyl lithium (2 6 mL, 4.6 mmol, 1.8M).After 45 minutes a solution of4-(3-ethoxy-4-methoxyphenyl)-3-buten-2-one (0.51 g, 2,3 mmol) in 10 mLof tetrahydrofuran was slowly added to the reaction mixture. After 1hour at −78° C. the mixture was allowed to warm to room temperature, Thereaction mixture was then carefully quenched with 10 mL of an aqueoussolution of ammonium chloride. The resulting mixture was extracted withmethylene chloride (3×10 mL). The combined organic extracts were driedover magnesium sulfate and concentrated in vacuo to afford 0.7 g of thecrude product. The crude product was purified by chromatography (silicagel, 2% ethyl acetate/methylene chloride) to afford 0.41 g (60%) of theproduct as an oil which solidified: mp 57-58° C.; ¹H NMR (CDCl₃) δ7.31-7.13 (m, 5H), 6.83-6.69 (m, 3H), 4.48 (t, J=7.5 Hz, 1H), 4.03 (q,J=7 Hz, 2H), 3.82 (s, 3H), 3.13 (d, J=7.5 Hz, 2H), 2.07 (s, 3H), 1.41(t, J=7 Hz, 3H); ¹³C NMR (CDCl₃) δ 207.0, 148.2, 148.0, 144.2, 136.4,128.6, 127.6, 126.4, 119.4, 113.0, 111.5, 64.3, 55.9, 49.9, 45.6, 30.6,14.8; Anal. Calcd for C₁₉H₂₂O₃. Theoretical: C, 76.48; H, 7.43. Found:C, 76.81; H, 7.44.

EXAMPLE 28 3-(3,4-Dimetboxyphenyl)-3-(naphth-1-yl)acrylonitrile

[0138] 1-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol),aluminum chloride (1.5 g, 11 mmol) and 1-naphthoyl chloride (1.5 mL, 10mmol) with a reaction time of 24 hours at room temperature. The crudeproduct was purified by flash column chromatography (silica gel, 2.5%ethyl acetate/methylene chloride) to afford 1.85 g (63%) of the productas a white solid: mp 92.5-94.5° C.; ¹H NMR (CDCl₃) δ 8.06-7.84 (m, 3H),7.80-7.39 (m, 5H), 7.31-7.21 (m, 1H), 6.84-6.74 (m, 1H), 3.94 (s, 3H),3.91 (s, 3H); ¹³C NMR (CDCl₃) δ 196.6, 153.5, 149.0, 136.8, 133.6,131.1, 130.9, 130.5, 128.2, 126.9, 126.7, 126.3, 126.3, 125.6, 124.3,111.3, 109.7, 56.0, 55.9; Anal. Calcd for C₁₉H₁₆O₃. Theoretical: C,78.06; H, 5.52. Found: C, 77.97; H, 5.66.3-(3,4-Dimethoxyphenyl)-3-(naphth-1-yl)acrylonitrile is prepared in afashion similar to that described in Example 20.

EXAMPLE 29 3-(3,4-Dimethoxyphenyl)-3-(2,5-dichlorophenyl)acrylonitrile

[0139] 2′,5′-Dichloro-3,4-dimethoxybenzophenone was prepared analogouslyto 3,4,3′,4′-tetramethoxybenzophenone using veratrole (2.15 mL, 15mmol), aluminum chloride (2.2 g, 16.5 mmol) and 2,5-dichlorobenzoylchloride (1.9 mL, 15 mmol) with a reaction time of 3 hours at reflux.The crude product was purified by flash column chromatography (silicagel, 2.5% ethyl acetate/methylene chloride) to afford 3.88 g (83%) ofthe product as a white solid: mp 129-130° C.; ¹H NMR (CDCl₃) δ 7.65-7.56(m, 1H), 7.41-7.12 (m, 4H), 6.89-6.81 (m, 1H), 3.96 (s, 3H), 3.94 (s,3H); ¹³C NMR (CDCl₃) δ 191.1, 154.4, 149.6, 137.9, 132.0, 130.5, 128.7,128.0, 125.7, 110.2, 56.1, 56.0; Anal. Calcd for C₁₅H₁₂C₁₂O₃.Theoretical: C, 57.90; H, 3.89. Found: C, 57.58; H, 3.87.

[0140]3-(3,4-Dimethoxyphenyl)-3-(2,5-dichlorophenyl)acrylonitrile isprepared in an analogous fashion as described in Example 26 startingwith 5′-dichloro-3,4-dimethoxybenzophenone.

EXAMPLE 30 2′,6′,3,4-Tetramethoxybenzophenone

[0141] 2′,6′,3,4-Tetramethoxybenzophenone was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone except using veratrole (1.3 mL, 10mmol), aluminum chloride (1.47 g, 11 mmol) and 2,6-dimethoxybenzoylchloride (2.0 mL, 10 mmol) with a reaction time of 24 hours at roomtemperature. The crude mixture was purified by flash columnchromatography (silica gel, 4% ethyl acetate/methylene chloride) toafford 2.11 g (70%) of the product as a white solid: mp 128-129° C.; ¹HNMR (CDCl₃) δ 7.66-7.60 (m, 1H), 7.40-7.20 (m, 2H), 6.88-6.79 (m, 1H),6.67-6.65 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.71 (s, 6H); ¹³C NMR(CDCl₃) δ 193.8, 157.4, 153.4, 148.9, 130.9, 130.5, 125.3, 118.0, 110.2,109.9, 104.0, 55.9, 55.8; Anal. Calcd for C₁₇H₁₈O₅. Theoretical: C,67.54; H, 6.00. Found: C, 66.51; H, 5.91.

[0142] 3-(3,4-Dimethoxyphenyl)-3-(2,6-dimethoxyphenyl)acrylonitrile isprepared in an analogous fashion as described in Example 10 startingwith 2′,6′,3,4-tetramethoxybenzophenone.

EXAMPLE 31

[0143] Tablets, each containing 50 milligrams of active ingredient, canbe prepared in the following manner: Constituents (for 1000 tablets)active ingredient 50.0 grams  lactose 50.7 grams  wheat starch 7.5 gramspolyethylene glycol 6000 5.0 grams talc 5.0 grams magnesium stearate 1.8grams demineralized water q.s.

[0144] The solid ingredients are first forced through a sieve of 0.6 mmmesh width. The active ingredient, the lactose, the talc, the magnesiumstearate and half of the starch then are mixed. The other half of thestarch is suspended in 40 milliliters of water and this suspension isadded to a boiling solution of the polyethylene glycol in 100milliliters of water. The resulting paste is added to the pulverulentsubstances and the mixture is granulated, if necessary with the additionof water. The granulate is dried overnight at 35° C., forced through asieve of 1.2 mm mesh width and compressed to form tablets ofapproximately 6 mm diameter which are concave on both sides.

EXAMPLE 32

[0145] Tablets, each containing 100 milligrams of active ingredient, canbe prepared in the following manner: Constituents (for 1000 tablets)active ingredient 100.0 grams lactose 100.0 grams wheat starch  47.0grams magnesium stearate  3.0 grams

[0146] All the solid ingredients are first forced through a sieve of 0.6mm mesh width. The active ingredient, the lactose, the magnesiumstearate and half of the starch then are mixed. The other half of thestarch is suspended in 40 milliliters of water and this suspension isadded to 100 milliliters of boiling water. The resulting paste is addedto the pulverulent substances and the mixture is granulated, ifnecessary with the addition of water. The granulate is dried overnightat 35° C., forced through a sieve of 1.2 mm mesh width and compressed toform tablets of approximately 6 mm diameter which are concave on bothsides.

EXAMPLE 33

[0147] Tablets for chewing, each containing 75 milligrams of activeingredient, can be prepared in the following manner: Composition (for1000 tablets) active ingredient 75.0 grams mannitol 230.0 grams  lactose150.0 grams  talc 21.0 grams glycine 12.5 grams stearic acid 10.0 gramssaccharin  1.5 grams 5% gelatin solution q.s.

[0148] All the solid ingredients are first forced through a sieve of0.25 mm mesh width. The mannitol and the lactose are mixed, granulatedwith the addition of gelatin solution, forced through a sieve of 2 mmmesh width, dried at 50° C. and again forced through a sieve of 1.7 mmmesh width. The active ingredient, the glycine and the saccharin arecarefully mixed, the mannitol, the lactose granulate, the stearic acidand the talc are added and the whole is mixed thoroughly and compressedto form tablets of approximately 10 mm diameter which are concave onboth sides and have a breaking groove on the upper side.

EXAMPLE 34

[0149] Tablets, each containing 10 milligrams of active ingredient, canbe prepared in the following manner: Composition (for 1000 tablets)active ingredient 10.0 grams lactose 328.5 grams  corn starch 17.5 gramspolyethylene glycol 6000  5.0 grams talc 25.0 grams magnesium stearate 4.0 grams demineralized water q.s.

[0150] The solid ingredients are first forced through a sieve of 0.6 mmmesh width. Then the active ingredient, lactose, talc, magnesiumstearate and half of the starch are intimately mixed. The other half ofthe starch is suspended in 65 milliliters of water and this suspensionis added to a boiling solution of the polyethylene glycol in 260milliliters of water. The resulting paste is added to the pulverulentsubstances, and the whole is mixed and granulated, if necessary with theaddition of water. The granulate is dried overnight at 35° C., forcedthrough a sieve of 1.2 mm mesh width and compressed to form tablets ofapproximately 10 mm diameter which are concave on both sides and have abreaking notch on the upper side.

EXAMPLE 35

[0151] Gelatin dry-filled capsules, each containing 100 milligrams ofactive ingredient, can be prepared in the following manner: Composition(for 1000 capsules) active ingredient 100.0 grams  microcrystallinecellulose 30.0 grams  sodium lauryl sulphate 2.0 grams magnesiumstearate 8.0 grams

[0152] The sodium lauryl sulphate is sieved into the active ingredientthrough a sieve of 0.2 mm mesh width and the two components areintimately mixed for 10 minutes. The microcrystalline cellulose is thenadded through a sieve of 0.9 mm mesh width and the whole is againintimately mixed for 10 minutes. Finally, the magnesium stearate isadded through a sieve of 0.8 mm width and, after mixing for a further 3minutes, the mixture is introduced in portions of 140 milligrams eachinto size 0 (elongated) gelatin dry-fill capsules.

EXAMPLE 36

[0153] A 0.2% injection or infusion solution can be prepared, forexample, in the following manner: active ingredient  5.0 grams sodiumchloride  22.5 grams phosphate buffer pH 7.4 300.0 grams demineralizedwater to 2500.0 milliliters

[0154] The active ingredient is dissolved in 1000 milliliters of waterand filtered through a micro-filter or slurried in 1000 mL of H₂O. Thebuffer solution is added and the whole is made up to 2500 milliliterswith water. To prepare dosage unit forms, portions of 1.0 or 2.5milliliters each are introduced into glass ampoules (each containingrespectively 2.0 or 5.0 milligrams of active ingredient).

What is claimed is:
 1. A compound of the formula:

in which: (a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0,1, 2, or 3, and R¹ is alkyl of one to 10 carbon atoms, monocycloalkyl ofup to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, orbenzocyclic alkyl of up to 10 carbon atoms, or (b) X is —CH═ and R¹ isalkylidene of up to 10 carbon atoms, monocycloalkylidene of up to 10carbon atoms, or bicycloalkylidene of up to 10 carbon atoms; R² ishydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, loweralkyl, lower alkylidenemethyl, lower alkoxy, or halo; R³ is (i) phenyl,unsubstituted or substituted with 1 or more substituents each selectedindependently from nitro, cyano, halo, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substitutedwith alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino,amino substituted with an alkyl of 1 to 5 carbon atoms, alkyl of up to10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10carbon atoms, cycloalkoxy of up to 10 carbon atoms, alkylidenemethyl ofup to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms,phenyl, or methylenedioxy; (ii) pyridine, substituted pyridine,pyrrolidine, imidizole, naphthalene, or thiophene; (iii) cycloalkyl of4-10 carbon atoms, unsubstituted or substituted with 1 or moresubstituents each selected independently from the group consisting ofnitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino,substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10carbon atoms, phenyl; each of R⁴ and R⁵ taken individually is hydrogenor R⁴ and R⁵ taken together are a carbon-carbon bond; Y is —COZ, —C≡N,or lower alkyl of 1 to 5 carbon atoms; Z is —OR, —NR⁶R⁶, —R⁷, or —OR⁷;R⁶ is hydrogen or lower alkyl; and R⁷ is alkyl or benzyl.
 2. A compoundaccording to claim 1 in which R¹ is alkyl, monocycloalkyl of up to 10carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclicalkyl of up to 10 carbon atoms; X is —(CH₂)_(n)— or —O—, where n=0, 1,2, or 3; R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, lower alkyl, lower alkoxy, halo; and R⁴, R⁵, Y, Z, R⁶,and R⁷ are as therein defined.
 3. A compound according to claim 1 inwhich R³ is (i) phenyl or naphthalene, unsubstituted or substituted with1 or more substituents each selected independently from nitro, cyano,halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 5 carbon atoms, alkyl or cycloalkyl of 1 to 10 carbon atoms, alkoxyor cycloalkoxy of 1 to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10carbon atoms, unsubstituted or substituted with one or more substituentseach selected independently from the group consisting of nitro, cyano,halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl.
 4. Acompound according to claim 1 which is a nitrile of the formula:

wherein: (a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1,2, or 3, and R¹ is alkyl of up to 10 carbon atoms, monocycloalkyl of upto 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, orbenzocyclic alkyl of up to 10 carbon atoms, or (b) X is —CH═, and R¹ isalkylidene of up to 10 carbon atoms or monocycloalkylidene of up to 10carbon atoms; R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbarnoyl, acetoxy, carboxy,hydroxy, amino, lower alkyl, lower alkoxy, or halo; and R³ is (i) phenylor naphthyl, unsubstituted or substituted with 1 or more substituentseach selected independently from nitro, cyano, halo, trifluoromethyl,carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoylsubstituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy,hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms,alkyl or cycloalkyl of 1 to 10 carbon atoms, alkoxy or cycloalkoxy of 1to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10 carbon atoms,unsubstituted or substituted with one or more substituents, eachselected independently from the group consisting of nitro, cyano, halo,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl.
 5. Acompound according to claim 1 which is a alkanoic acid derivative of theformula:

wherein: (a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1,2, or 3, and R¹ is alkyl of up to 10 carbon atoms, monocycloalkyl of upto 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, orbenzocyclic alkyl of up to 10 carbon atoms, or (b) X is —CH═, and R¹ isalkylidene of up to 10 carbon atoms or monocycloalkylidene of up to 10carbon atoms; R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, lower alkyl, lower alkoxy, or halo; R³ is (i) phenyl ornaphthyl, unsubstituted or substituted with one or more substituentseach selected independently from nitro, cyano, halo, trifluoromethyl,carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoylsubstituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy,hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms,alkyl or cycloalkyl of 1 to 10 carbon atoms, alkoxy or cycloalkoxy of 1to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10 carbon atoms,unsubstituted or substituted with one or more substituents each selectedindependently from the group consisting of nitro, cyano, halo,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl; and Zis —OH, —NR⁶R⁶, R⁷, or —OR⁷ in which R⁶ is hydrogen or lower alkyl; andR⁷ is alkyl or benzyl.
 6. A compound according to claim 1 which is3,3-bis-(3,4-dimethoxyphenyl)-acrylonitrile,3,3-bis-(3-ethoxy-4-methoxyphenyl)acrylonitrile, methyl3,3-bis-(3-ethoxy-4-methoxyphenyl)-propenoate, methyl3-(3-ethoxy-4-methoxyphenyl)-3-pheiiylpropenoate,3-(3-propoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3,3-bis-(3-cyclopentoxy-4-methoxyphenyl)acrylonitrile, methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropenoate,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropene,1-(3-cyclopentoxy-4-methoxyphenyl)-1-phenylpropane,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanoate,3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanoate,3,3-bis-(3,4-dimethoxyphenyl)propanenitrile,3,3-bis-(3-ethoxy-4-methoxyphenyl)propanenitrile,3-(3,4-dimethoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-metboxyphenyl)-3-naphthylpropanenitrile,3-(3,4-dimethoxyphenyl)-3-phenylpropanenitrile, or3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)-propanenitrile. 7.A compound according to claim 1 which is4,4-bis-(3,4-dimethoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-phenylbut-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-cyclopentoxy-4-methoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-indan2-yloxy-4-methoxyphenyl)but-3-en-2-one;4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)but-3-en-2-one;4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one;4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)but-3-en-2-one;4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)-butan-2-one; methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enoate; methyl3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enoate; methyl3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanoate4-(3-ethoxy-4-methoxyphenyl)-4-(2-furyl)but-3-en-2-one;3-(3-ethoxy-4-methoxyphenyl)-3-(2-furyl)prop-2-enenitrile;3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)but-3-en-2-one;4,4-bis-(3,4-dimethoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)butan-2-one;4,4-bis-(3-ethoxy-4-methoxyphenyl)but-3-en-2-one;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenylprop-2-enenitrile;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pentan-3-one;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pent-1-en-3-one;1,1-bis-(3,4-dimethoxyphenyl)pentan-3-one;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-propanenitrile;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanenitrile;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enamide;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl-3-phenyl)propanamide;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanamide;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enamide;3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)prop-2-enamide;3,3-bis-(3-ethoxy-4-methoxyphenyl)prop-2-enamide;3,3-bis-(3,4-dimethoxyphenyl)prop-2-enamide;3,3-bis-(3-ethoxy-4-methoxyphenyl)propanamide;3,3-bis-(3,4-dimethoxyphenyl)propanamide;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-exo-norbornyloxyphenyl)but-3-en-2-one;3-(3,4-dimethoxyphenyl)-3-(4-metboxy-3-exo-norbornyloxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)prop-2-enenitrile;3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile; or3-(4-aminophenyl)-3-(3-ethoxy-4-dimethoxyphenyl)prop-2-enenitrile.
 8. Amethod which comprises administering to a mammal an amount of a compoundaccording to claim 1 which amount is effective to inhibit at least oneof the enzymatic action of phosphodiesterase, the level of TNF_(α) andtranslocation of NFκB to the nucleus which comprises reducing the levelsof phosphodiesterases, TNF_(α) and NFκB in mammals by administeringthereto an effective amount of a compound according to claim
 1. 9. Apharmaceutical composition comprising a compound according to claim 1 inan amount effective upon single or multiple dosage to to inhibit atleast one of the enzymatic action of phosphodiesterase, the level ofTNF_(α) and translocation of NFκB to the nucleus, in combination with apharmaceutical carrier.